Pecvd coating methods for capped syringes, cartridges and other articles

ABSTRACT

A method is disclosed in which a vapor-deposited coating or layer is directly or indirectly applied to at least a portion of the internal wall of the barrel of a capped pre-assembly comprising a barrel, optionally a dispensing portion, and a cap. The cap is secured to the barrel and at least substantially isolates the distal opening of the dispensing portion from pressure conditions outside the cap. A vapor-deposited coating or layer is applied directly or indirectly to at least a portion of the internal wall of the barrel while the pre-assembly is capped. The coating or layer is applied under conditions effective to maintain communication from the barrel lumen to the exterior via the front opening, optionally further via the dispensing portion lumen if present, at the end of the applying step. The capped pre-assembly can be pressure tested easily and rapidly, for example with a test duration between 1 and 60 seconds, to determine whether it has container closure integrity.

This application is a continuation in part of

-   U.S. Ser. No. 13/169,811, filed Jun. 27, 2011, now pending;    -   which is a divisional of-   U.S. Ser. No. 12/779,007, filed May 12, 2010, now U.S. Pat. No.    7,985,188;    -   which claims the priority of:-   U.S. Provisional Ser. No. 61/222,727, filed Jul. 2, 2009;-   U.S. Provisional Ser. No. 61/213,904, filed Jul. 24, 2009;-   U.S. Provisional Ser. No. 61/234,505, filed Aug. 17, 2009;-   U.S. Provisional Ser. No. 61/261,321, filed Nov. 14, 2009;-   U.S. Provisional Ser. No. 61/263,289, filed Nov. 20, 2009;-   U.S. Provisional Ser. No. 61/285,813, filed Dec. 11, 2009;-   U.S. Provisional Ser. No. 61/298,159, filed Jan. 25, 2010;-   U.S. Provisional Ser. No. 61/299,888, filed Jan. 29, 2010;-   U.S. Provisional Ser. No. 61/318,197, filed Mar. 26, 2010; and-   U.S. Provisional Ser. No. 61/333,625, filed May 11, 2010;    and this application claims the priority of:-   U.S. Provisional Ser. No. 61/636,377, filed Apr. 20, 2012.

All of the above patent applications and patent are incorporated here byreference in their entirety, including the applications they incorporateby reference.

FIELD OF THE INVENTION

The present invention relates to the technical field of coated surfaces,for example interior surfaces of pharmaceutical packages or othervessels for storing or other contact with fluids. Examples of suitablefluids include foods or biologically active compounds or body fluids,for example blood. The present invention also relates to apharmaceutical package or other vessel and to a method for coating orlayer an inner or interior surface of a pharmaceutical package or othervessel. The present invention also relates more generally to medicaldevices, including devices other than packages or vessels, for examplecatheters.

The present disclosure also relates to improved methods for processingpharmaceutical packages or other vessels, for example multiple identicalpharmaceutical packages or other vessels used for pharmaceuticalpreparation storage and delivery, venipuncture and other medical samplecollection, and other purposes. Such pharmaceutical packages or othervessels are used in large numbers for these purposes, and must berelatively economical to manufacture and yet highly reliable in storageand use.

BACKGROUND OF THE INVENTION

One important consideration in manufacturing pre-filled syringes andcartridges or other vessels (such as vials) for storing or other contactwith fluids, for example, is that the contents of the pharmaceuticalpackage or other vessel desirably will have a substantial shelf life.During this shelf life, it is important to isolate the material fillingthe pharmaceutical package or other vessel from the vessel wallcontaining it, or from barrier coating or layers or other functionalcoating or layers applied to the pharmaceutical package or other vesselwall to avoid leaching material from the pharmaceutical package or othervessel wall, barrier coating or layer, or other functional coating orlayers into the prefilled contents or vice versa.

Commonly, after it is filled, a prefilled syringe or cartridge is cappedat the distal end, as with a needle shield or other type of cap, and isclosed at the proximal end by its drawn plunger tip or piston. Theprefilled syringe or cartridge can be wrapped in a sterile packagebefore use. To use the prefilled syringe or cartridge, the packaging andneedle shield or other type of cap are removed, optionally a hypodermicneedle or other type of dispenser is attached (if not already present),the delivery conduit or syringe is moved to a use position (such as byinserting the hypodermic needle into a patient's blood vessel or intoapparatus to be rinsed with the contents of the syringe), and theplunger tip or piston is advanced in the barrel to inject the contentsof the barrel. If a cartridge is being used, it is also placed into amechanism that mechanically advances the piston to make an injection,for example using an injection spring.

An important consideration regarding medical syringes and cartridges, inparticular prefilled syringes and cartridges, is to ensure that theprefilled syringe or cartridge has container closure integrity, meaningthat it has been determined to be sterile, and not subject to subsequentmicrobiological contamination, by a mechanical, non-destructive testmethod. Other important considerations are that when the syringe orcartridge is being manufactured and before it has been filled, it doesnot have defects that would prevent the filled package from having thenecessary container closure integrity. It is also important tomanufacture a medical syringe or cartridge that is economical tomanufacture, yet will provide the necessary container closure integrity,which can be verified by a test performed on every piece manufactured (aconcept sometimes referred to as “100% inspection”).

SUMMARY OF THE INVENTION

An aspect of the invention is a method in which a vapor-depositedcoating or layer is directly or indirectly applied to at least a portionof the internal wall of the barrel of a capped pre-assembly.

A capped pre-assembly is provided comprising a barrel, optionally adispensing portion, and a cap.

The barrel has an internal wall defining a barrel lumen and a frontopening through the internal wall.

The optional dispensing portion can be secured to the barrel andincludes a distal opening and a dispensing portion lumen. The distalopening is located outside the barrel. The dispensing portion lumencommunicates between the front opening of the barrel and the distalopening of the dispensing portion.

The cap is secured to the barrel and at least substantially isolates thefront opening of the barrel and (if a dispensing portion is present) thedistal opening of the dispensing portion from pressure conditionsoutside the cap.

A vapor-deposited coating or layer is applied directly or indirectly toat least a portion of the internal wall of the barrel. The coating orlayer is applied while the pre-assembly is capped. The coating or layeris applied under conditions effective to maintain communication betweenthe barrel lumen and the exterior via the front opening at the end ofthe applying step.

In an optional further elaboration of the method, the cappedpre-assembly can be pressure tested easily and rapidly, for example witha test duration between 1 and 60 seconds, to determine whether it hascontainer closure integrity.

Other aspects of the invention will become apparent from the presentdescription, claims, and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevation view of a capped pre-assembly according to anembodiment of the disclosure.

FIG. 2 is a longitudinal section of the capped pre-assembly of FIG. 1.

FIG. 3 is an enlarged fragmentary view of the capped pre-assembly ofFIGS. 1 and 2.

FIG. 4 is a schematic longitudinal section of the capped pre-assembly ofFIGS. 1 and 2 seated on a chemical vapor deposition coating station.

FIG. 5 is a section taken along section lines A-A of FIG. 4.

FIG. 6 is a schematic view showing more details of the chemical vapordeposition coating station shown in FIGS. 4 and 5.

FIG. 7 is a view similar to FIG. 2 of the capped pre-assembly of FIGS.1-6, filled with a pharmaceutical preparation and fitted with a plungertip or piston to define a pre-filled syringe. In the option shown, aplunger tip and plunger are installed.

FIG. 8 is a plot of pressure decay for 14 different samples madeaccording to the working example set out below.

The following reference characters are used in the drawing figures:

12 Capped pre-assembly 14 Barrel 16 Internal wall 18 Barrel lumen 20Dispensing portion 22 Front opening 24 Distal opening 26 Dispensingportion lumen 27 Cap 30 (first) Vapor-deposited coating or layer 32Opening 34 (second) vapor-deposited coating or layer 36 Plunger tip orpiston 38 Plunger rod 40 Fluid material 42 Rib 44 Cylindrical surface 46Barb 48 Catch 50 Vessel holder 52 Plot 54 Plot 60 coating station 82Opening 84 Closed end 92 Vessel port 94 Vacuum duct 96 Vacuum port 98Vacuum source 100 O-ring (of 92) 102 O-ring (of 96) 104 Gas inlet port106 O-ring (of 100) 108 Probe (counter electrode) 110 Gas delivery port(of 108) 114 Housing (of 50 or 112) 116 Collar 118 Exterior surface (of80) 144 PECVD gas source 152 Pressure gauge 160 Electrode 162 Powersupply 164 Sidewall (of 160) 166 Sidewall (of 160) 168 Closed end (of160) 200 Electrode 210 Pharmaceutical package 404 Exhaust 574 Mainvacuum valve 576 Vacuum line 578 Manual bypass valve 580 Bypass line 582Vent valve 584 Main reactant gas valve 586 Main reactant feed line 588Organosilicon liquid reservoir 590 Organosilicon feed line (capillary)592 Organosilicon shut-off valve 594 Oxygen tank 596 Oxygen feed line598 Mass flow controller 600 Oxygen shut-off valve 602 Additionalreservoir 604 Feed line 606 Shut-off valve 614 Headspace 616 Pressuresource 618 Pressure line 620 Capillary connection

The present invention will now be described more fully, with referenceto the accompanying drawings, in which several embodiments are shown.This invention can, however, be embodied in many different forms andshould not be construed as limited to the embodiments set forth here.Rather, these embodiments are examples of the invention, which has thefull scope indicated by the language of the claims. Like numbers referto like or corresponding elements throughout. The following disclosurerelates to all embodiments unless specifically limited to a certainembodiment.

DEFINITION SECTION

In the context of the present invention, the following definitions andabbreviations are used:

In the present Figures, the capped pre-assembly 12 is configured as asyringe. The capped pre-assembly 12 can optionally be completed to forma syringe by adding a plunger tip or piston 36 (two interchangeablenames for the same structure) and a plunger rod 38. The internal wall 16can define at least a portion of the barrel 14. The plunger tip orpiston 36 can be a relatively sliding part of the syringe, with respectto the barrel 14. The term “syringe,” however, is broadly defined toinclude cartridges, injection “pens,” and other types of barrels orreservoirs adapted to be assembled with one or more other components toprovide a functional syringe. “Syringe” is also broadly defined toinclude related articles such as auto-injectors, which provide amechanism for dispensing the contents.

RF is radio frequency.

The term “at least” in the context of the present invention means “equalor more” than the integer following the term. The word “comprising” doesnot exclude other elements or steps, and the indefinite article “a” or“an” does not exclude a plurality unless indicated otherwise. Whenever aparameter range is indicated, it is intended to disclose the parametervalues given as limits of the range and all values of the parameterfalling within said range.

“First” and “second” or similar references to, for example, coating orlayers refer to the minimum number of coating or layers that arepresent, but do not necessarily represent the order or total number ofcoating or layers. These terms do not limit the number of coating orlayers or the particular processing carried out at the respectivestations.

For purposes of the present invention, a “precursor” is a compoundhaving at least one of the linkages:

which is a tetravalent silicon atom connected to an oxygen or nitrogenatom and an organic carbon atom (an organic carbon atom being a carbonatom bonded to at least one hydrogen atom). A volatile organosiliconprecursor, defined as such a precursor that can be supplied as a vaporin a PECVD apparatus, is an optional organosilicon precursor.Optionally, the organosilicon precursor is selected from the groupconsisting of a linear siloxane, a monocyclic siloxane, a polycyclicsiloxane, a polysilsesquioxane, an alkyl trimethoxysilane, a linearsilazane, a monocyclic silazane, a polycyclic silazane, apolysilsesquiazane, and a combination of any two or more of theseprecursors.

The feed amounts of PECVD precursors, gaseous reactant or process gases,and carrier gas are sometimes expressed in “standard volumes” in thespecification and claims. The standard volume of a charge or other fixedamount of gas is the volume the fixed amount of the gas would occupy ata standard temperature and pressure (without regard to the actualtemperature and pressure of delivery). Standard volumes can be measuredusing different units of volume, and still be within the scope of thepresent disclosure and claims. For example, the same fixed amount of gascould be expressed as the number of standard cubic centimeters, thenumber of standard cubic meters, or the number of standard cubic feet.Standard volumes can also be defined using different standardtemperatures and pressures, and still be within the scope of the presentdisclosure and claims. For example, the standard temperature might be 0°C. and the standard pressure might be 760 Torr (as is conventional), orthe standard temperature might be 20° C. and the standard pressure mightbe 1 Torr. But whatever standard is used in a given case, when comparingrelative amounts of two or more different gases without specifyingparticular parameters, the same units of volume, standard temperature,and standard pressure are to be used relative to each gas, unlessotherwise indicated.

The corresponding feed rates of PECVD precursors, gaseous reactant orprocess gases, and carrier gas are expressed in standard volumes perunit of time in the specification. For example, in the working examplesthe flow rates are expressed as standard cubic centimeters per minute,abbreviated as sccm. As with the other parameters, other units of timecan be used, such as seconds or hours, but consistent parameters are tobe used when comparing the flow rates of two or more gases, unlessotherwise indicated.

The term “at least” in the context of the present invention means “equalor more” than the integer following the term. Thus, a barrel anddispensing portion in the context of the present invention has one ormore openings. One or two openings, like the openings of a sample tube(one opening) or a syringe barrel (two openings) are preferred. If thevessel has two openings, they can be of same or different size. If thereis more than one opening, one opening can be used for the gas inlet fora PECVD coating or layer method according to the present invention,while the other openings are capped.

Empirical compositions represented by the formulas SiO_(x),SiO_(x)C_(y), and SiO_(x)C_(y)H_(z) are referred to in thisspecification. The values of x, y, and z used throughout thisspecification should be understood as ratios or an empirical formula(for example for a coating or layer), rather than as a limit on thenumber or type of atoms in a molecule. For example,octamethylcyclotetrasiloxane, which has the molecular compositionSi₄O₄C₈H₂₄, can be described by the following empirical formula, arrivedat by dividing each of w, x, y, and z in the molecular formula by 4, thelargest common factor: SiO₁C₂H₆. The values of x, y, and z are also notlimited to integers. For example, (acyclic) octamethyltrisiloxane,molecular composition Si₃O₂C₈H₂₄, is reducible to SiO_(0.67)C_(2.67)H₈.Also, although SiO_(x)C_(y)H_(z) is described as equivalent toSiO_(x)C_(y), it is not necessary to show the presence of hydrogen inany proportion to show the presence of SiO_(x)C_(y).

A “protective coating or layer” according to the present invention is acoating or layer that protects an underlying surface, coating or layerfrom a fluid composition contacting the coating or layer. The present pHprotective coating or layers optionally can have a composition accordingto the empirical composition Si_(w)O_(x)C_(y)H_(z), (or its equivalentSiO_(x)C_(y)) as defined herein. It generally has an atomic ratioSi_(w)O_(x)C_(y) (or its equivalent SiO_(x)C_(y)) wherein w is 1, x isfrom about 0.5 to about 2.4, y is from about 0.6 to about 3.

Typically, expressed as the formula Si_(w)O_(x)C_(y), the atomic ratiosof Si, O, and C in the “protective coating or layer” are, as severaloptions:

Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);

Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)

Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to 1.5)

Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to 1.4), or

Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to 1.33)

The atomic ratio can be determined by XPS (X-ray photoelectronspectroscopy). Taking into account the H atoms, which are not measuredby XPS, the coating or layer may thus in one aspect have the formulaSi_(w)O_(x)C_(y)H_(z) (or its equivalent SiO_(x)C_(y)), for examplewhere w is 1, x is from about 0.5 to about 2.4, y is from about 0.6 toabout 3, and z is from about 2 to about 9. Typically, such coating orlayer would hence contain 36% to 41% carbon normalized to 100% carbonplus oxygen plus silicon.

One of the optional embodiments of the present invention is a syringepart, for example a syringe or cartridge barrel, particularly as part ofa capped pre-assembly, coated with a pH protective coating or layer.

“Slidably” means that the plunger tip or piston, closure, or othermovable part is permitted to slide in a syringe barrel, cartridge, orother vessel.

DETAILED DESCRIPTION

Referring to the Figures, an aspect of the invention is a method inwhich a vapor-deposited coating or layer 30 is directly or indirectlyapplied to at least a portion of the internal wall 16 of the barrel 14of a capped pre-assembly 12.

A capped pre-assembly 12 is provided comprising a barrel 14, optionallya dispensing portion 20, and a cap 28. The capped pre-assembly 12 can bea complete article or it can be a portion of a complete article adaptedto dispense fluid, such as a syringe, a cartridge, a catheter, or otherarticle.

The barrel 14 has an internal wall 16 defining a barrel lumen 18 and afront opening 22 through the internal wall 16. Optionally in anyembodiment, the barrel 14 can further include a another opening 32spaced from the dispensing portion 20 and communicating through theinternal wall 16. Such an opening is conventional, for example, in asyringe or cartridge, where a typical example is the back opening 32 ofa prefilled syringe barrel, through which the piston or plunger 36 isinserted after the barrel lumen 18 is filled with a suitablepharmaceutical preparation or other fluid material 40 to be dispensed.

The barrel 14 is formed, for example, by molding, although the manner ofits formation is not critical and it can also be formed, for example, bymachining a solid preform. Preferably, the barrel is molded by injectionmolding thermoplastic material, although it can also be formed by blowmolding or a combined method.

As one preferred example, the barrel 14 can be formed by placing adispensing portion 20 as described below in an injection mold andinjection molding thermoplastic material about the dispensing portion,thus forming the barrel and securing the dispensing portion to thebarrel. Alternatively, the dispensing portion (if present) and thebarrel can be molded or otherwise formed as a single piece, or can beformed separately and joined in other ways. The barrel of any embodimentcan be made of any suitable material. Several barrel materialsparticularly contemplated are COC (cyclic olefin copolymer), COP (cyclicolefin polymer), PET (polyethylene terephthalate), and polypropylene.

The optional dispensing portion 20 of the capped pre-assembly 12 isprovided to serve as an outlet for fluid dispensed from the barrel lumen18 of a completed article made from the capped pre-assembly 12. Oneexample of a suitable dispensing portion illustrated in the Figures is ahypodermic needle 20.

Alternatively, in any embodiment the dispensing portion 20 can insteadbe a needle-free dispenser. One example of a suitable needle-freedispenser is a blunt or flexible dispensing portion intended to bereceived in a complementary coupling to transfer fluid material 40. Suchblunt or flexible dispensing portions are well known for use insyringes, intravenous infusion systems, and other systems and equipmentto dispense material while avoiding the hazard of working with a sharpneedle that may accidentally stick a health professional or otherperson. Another example of a needle-free dispenser is a fluid jet orspray injection system that injects a free jet or spray of fluiddirectly through a patient's skin, without the need for an intermediateneedle. Any type of dispensing portion 20, whether a hypodermic needleor any form of needle-free dispenser, is contemplated for use accordingto any embodiment of the present invention.

The dispensing portion 20 is secured to the barrel 14 and includes adistal opening 24 and a dispensing portion lumen 26. The front opening22 communicates with the barrel lumen 18. The distal opening 24 islocated outside the barrel 14. The dispensing portion lumen 26communicates between the front opening 22 and the distal opening 24 ofthe dispensing portion 20. In the illustrated embodiment, the distalopening 24 is at the sharpened tip of a hypodermic needle 20.

The cap 28 is secured to the barrel 14 and at least substantiallyisolates the front opening 22 and the distal opening 24 of thedispensing portion 20 from pressure conditions outside the cap 28.Optionally in any embodiment, the cap 28 sufficiently isolates portionsof the assembly 12 to provide a sufficient bio-barrier to facilitatesafe use of the capped pre-assembly 12 for transdermal injections.

The cap 28 can isolate the distal opening 24 in various ways. Effectiveisolation can be provided at least partially due to contact between thecap 28 and the distal opening 24, as shown in present FIGS. 2, 3, 4, and7. In the illustrated embodiment, the tip of the dispensing portion 20is buried in the material of the cap 28. Alternatively in anyembodiment, effective isolation can be provided at least partially dueto contact between the cap 28 and the barrel 14, as also shown inpresent FIGS. 2, 3, 4, and 7. In the illustrated embodiment, the primaryline of contact between the cap 28 and the barrel 14 is at a rib 42(best seen in FIG. 3) encircling and seated against a generallycylindrical surface 44 at the nose of the barrel 14. Alternatively inany embodiment, effective isolation can be provided due to both of thesetypes of contact as illustrated in FIGS. 2-3, or in other ways, withoutlimitation.

The cap 28 of any embodiment optionally has a latching mechanism, bestshown in FIG. 3, including a barb 46 and a catch 48 which engage to holdthe cap 28 in place. The catch 48 is made of sufficiently resilientmaterial to allow the cap 28 to be removed and replaced easily.

If the dispensing portion 20 is a hypodermic needle, the cap 28 can be aspecially formed needle shield. The original use of a needle shield isto cover the hypodermic needle before use, preventing accidental needlesticks and preventing contamination of the needle before it is injectedin a patient or an injection port. A comparable cap preferably is used,even if the dispensing portion 20 is a needle-free dispenser, to preventcontamination of the dispenser during handling.

The cap 28 can be formed in any suitable way. For example, the cap 28can be formed by molding thermoplastic material. Optionally in anyembodiment, the thermoplastic material is elastomeric material or othermaterial that is suitable for forming a seal. One suitable category ofelastomeric materials is known generically as thermoplastic elastomer(TPE). An example of a suitable thermoplastic elastomer for making a cap28 is Stelmi® Formulation 4800 (flexible cap formulation). Any othermaterial having suitable characteristics can instead be used in anyembodiment.

As another optional feature in any embodiment the cap 28 can besufficiently permeable to a sterilizing gas to sterilize the portions ofthe assembly 12 isolated by the cap. One example of a suitablesterilizing gas is ethylene oxide. Caps 28 are available that aresufficiently permeable to the sterilizing gas that parts isolated by thecap can nonetheless be sterilized. An example of a cap formulationsufficiently permeable to accommodate ethylene oxide gas sterilizationis Stelmi® Formulation 4800.

Thus, an optional step in the present methods is sterilizing the cappedpre-assembly 12 using a sterilizing gas. Sterilization can be performedat any suitable step, such as sterilizing the capped pre-assembly 12alone or sterilizing a complete pre-filled syringe assembly after it isfilled with a suitable pharmaceutical preparation or other material.

When carrying out the present method, a vapor-deposited coating or layer30 is applied directly or indirectly to at least a portion of theinternal wall 16 of the barrel 14. The coating or layer 30 is appliedwhile the pre-assembly 12 is capped. The coating or layer 30 is appliedunder conditions effective to maintain communication between the barrellumen 18 and the dispensing portion lumen 26 via the front opening 22 atthe end of the applying step.

In any embodiment the vapor-deposited coating or layer 30 optionally canbe applied through the opening 32.

In any embodiment the vapor-deposited coating or layer 30 optionally canbe applied by introducing a vapor-phase precursor material through theopening and employing chemical vapor deposition to deposit a reactionproduct of the precursor material on the internal wall of the barrel.

In any embodiment the vapor-deposited coating or layer (30) optionallycan be applied by flowing a precursor reactant vapor material throughthe opening and employing chemical vapor deposition to deposit areaction product of the precursor reactant vapor material on theinternal wall of the barrel.

In any embodiment the reactant vapor material optionally can be aprecursor.

In any embodiment the reactant vapor material optionally can be anorganosilicon precursor.

In any embodiment the reactant vapor material optionally can be anoxidant gas.

In any embodiment the reactant vapor material optionally can be oxygen.

In any embodiment the reactant vapor material optionally can include acarrier gas.

In any embodiment the reactant vapor material optionally can includehelium, argon, krypton, xenon, neon, or a combination of two or more ofthese.

In any embodiment the reactant vapor material optionally can includeargon.

In any embodiment the reactant vapor material optionally can be aprecursor material mixture with one or more oxidant gases in a partialvacuum through the opening and employing chemical vapor deposition todeposit a reaction product of the precursor material mixture on theinternal wall of the barrel.

In any embodiment the reactant vapor material optionally can be passedthrough the opening at sub-atmospheric pressure.

In any embodiment the chemical vapor deposition optionally can beplasma-enhanced chemical vapor deposition.

In any embodiment the vapor-deposited coating or layer optionally can bea gas barrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can bean oxygen barrier coating or layer.

In any embodiment the vapor-deposited coating or layer is a water vaporbarrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can bea solvent barrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can bea water barrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can bea solvent barrier coating or layer for a solvent comprising a co-solventused to increase drug solubilization.

In any embodiment the vapor-deposited coating or layer optionally can bea barrier coating or layer for water, glycerin, propylene glycol,methanol, ethanol, n-propanol, isopropanol, acetone, benzyl alcohol,polyethylene glycol, cotton seed oil, benzene, dioxane, or combinationsof any two or more of these.

In any embodiment the vapor-deposited coating or layer optionally can bea solute barrier coating or layer. Examples of solutes in drugs usefullyexcluded by a barrier layer in any embodiment include antibacterialpreservatives, antioxidants, chelating agents, pH buffers, andcombinations of any of these.

In any embodiment the vapor-deposited coating or layer optionally can bea metal ion barrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can bea barrel wall material barrier coating or layer, to prevent or reducethe leaching of barrel material such as any of the base barrel resinsmentioned previously and any other ingredients in their respectivecompositions.

The vapor deposited coating or layer for any embodiment defined in thisspecification (unless otherwise specified in a particular instance)optionally can be a coating or layer, optionally applied by PECVD asindicated in U.S. Pat. No. 7,985,188. The vapor deposited coating orlayer can be a barrier coating or layer, optionally a barrier coating orlayer characterized as an “SiO_(x)” coating or layer containing silicon,oxygen, and optionally other elements, in which x, the ratio of oxygento silicon atoms, optionally can be from about 1.5 to about 2.9, or 1.5to about 2.6, or about 2. These alternative definitions of x apply toany use of the term SiO_(x) in this specification. The barrier coatingor layer optionally can be applied, for example to the interior of apharmaceutical package or other vessel, for example a sample collectiontube, a syringe barrel, a vial, or another type of vessel. The SiO_(x)coating or layer is particularly contemplated as a barrier to oxygeningress or egress and a solute barrier to prevent migration of drugconstituents (as in the barrel lumen 18 of a prefilled syringe orcartridge) into the barrel wall or the migration of barrel wallconstituents into the drug or other contents of the barrel lumen.

In any embodiment plasma optionally can be generated in the barrel lumen18 by placing an inner electrode into the barrel lumen 18 through theopening 32, placing an outer electrode outside the barrel 14 and usingthe electrodes to apply plasma-inducing electromagnetic energy whichoptionally can be microwave energy, radio frequency energy, or both inthe barrel lumen 18.

In any embodiment the electromagnetic energy optionally can be directcurrent.

In any embodiment the electromagnetic energy optionally can bealternating current. The alternating current optionally can be modulatedat frequencies including audio, or microwave, or radio, or a combinationof two or more of audio, microwave, or radio.

In any embodiment the electromagnetic energy optionally can be appliedacross the barrel lumen (18).

In any embodiment, in addition to applying a first coating or layer asdescribed above, the method optionally can include applying second orfurther coating or layer of the same material or a different material.As one example useful in any embodiment, particularly contemplated ifthe first coating or layer is an SiO_(x) barrier coating or layer, afurther coating or layer can be placed directly or indirectly over thebarrier coating or layer. One example of such a further coating or layeruseful in any embodiment is a pH protective coating or layer

The pH protective coating or layer optionally can be applied over atleast a portion of the SiO_(x) coating or layer to protect the SiO_(x)coating or layer from contents stored in a vessel, where the contentsotherwise would be in contact with the SiO_(x) coating or layer. The pHprotective coating or layers or layers are particularly contemplated toprotect an SiOx barrier layer of a prefilled syringe or cartridge thatis exposed to contents, such as a pharmaceutical preparation, having apH between 4 and 9, alternatively between 4 and 8, alternatively between5 and 9. Such pharmaceutical preparations have been found to attack andremove the SiOx coating or layer if unprotected by a protective coatingor layer.

Thus, in any embodiment, after the applying step, anothervapor-deposited coating 34 optionally can be applied directly orindirectly over the coating 30, while the pre-assembly 12 is capped,under conditions effective to maintain communication between the barrellumen 18 and the dispensing portion lumen 26 via the front opening 22 atthe end of applying the second vapor-deposited coating 34.

In any embodiment, the other vapor-deposited coating 34 can be a pHprotective coating or layer.

In any embodiment, the pH protective coating or layer can include orconsist essentially of SiO_(x)C_(y) or SiN_(x)C_(y) wherein x is fromabout 0.5 to about 2.4, optionally about 1.1, and y is from about 0.6 toabout 3, optionally about 1.1.

In any embodiment, the pH protective coating or layer can include orconsist essentially of SiO_(x)C_(y)H_(z), in which x is from about 0.5to about 2.4, optionally from about 0.5 to 1, y is from about 0.6 toabout 3, optionally from about 2 to about 3, and z is from about 2 toabout 9, optionally from 6 to about 9.

Optionally in any embodiment, the pH protective coating or layer can beapplied as the first or sole vapor-deposited coating or layer (30),instead of or in addition to its application as a further layer. Thisexpedient may be useful, for example, where the barrel is made of glass.The presently disclosed pH protective coating or layer also reduces thedissolution of glass by contents having the pH values indicated asattacking SiO_(x) coatings or layers.

Surprisingly, it has been found that the above stated coatings or layerscan be applied to the capped pre-assembly 12 with substantially nodeposition of the vapor-deposited coating 30 in the dispensing portionlumen 26. This is shown by a working example below.

Precursors

The precursor for the SiO_(x) barrier coating or layer or for the pHprotective coating or layer can include any of the following precursorsuseful for PECVD. The precursor for the PECVD pH protective coating orlayer of the present invention optionally can be broadly defined as anorganometallic precursor. An organometallic precursor is defined in thisspecification as comprehending compounds of metal elements from GroupIII and/or Group IV of the Periodic Table having organic residues, forexample hydrocarbon, aminocarbon or oxycarbon residues. Organometalliccompounds as presently defined include any precursor having organicmoieties bonded to silicon or other Group III/IV metal atoms directly,or optionally bonded through oxygen or nitrogen atoms. The relevantelements of Group III of the Periodic Table are Boron, Aluminum,Gallium, Indium, Thallium, Scandium, Yttrium, and Lanthanum, Aluminumand Boron being preferred. The relevant elements of Group IV of thePeriodic Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium,Hafnium, and Thorium, with Silicon and Tin being preferred. Othervolatile organic compounds can also be contemplated. However,organosilicon compounds are preferred for performing present invention.

An organosilicon precursor is contemplated, where an “organosiliconprecursor” is defined throughout this specification most broadly as acompound having at least one of the linkages:

The first structure immediately above is a tetravalent silicon atomconnected to an oxygen atom and an organic carbon atom (an organiccarbon atom being a carbon atom bonded to at least one hydrogen atom).The second structure immediately above is a tetravalent silicon atomconnected to an —NH— linkage and an organic carbon atom (an organiccarbon atom being a carbon atom bonded to at least one hydrogen atom).Optionally, the organosilicon precursor is selected from the groupconsisting of a linear siloxane, a monocyclic siloxane, a polycyclicsiloxane, a polysilsesquioxane, a linear silazane, a monocyclicsilazane, a polycyclic silazane, a polysilsesquiazane, and a combinationof any two or more of these precursors. Also contemplated as aprecursor, though not within the two formulas immediately above, is analkyl trimethoxysilane.

If an oxygen-containing precursor (for example a Siloxane) is used, arepresentative predicted empirical composition resulting from PECVDunder conditions forming a hydrophobic or lubricating pH protectivecoating or layer would be Si_(w)O_(x)C_(y)H_(z) or its equivalentSiO_(x)C_(y) as defined in the Definition Section, while arepresentative predicted empirical composition resulting from PECVDunder conditions forming a barrier coating or layer would be SiO_(x),where x in this formula is from about 1.5 to about 2.9. If anitrogen-containing precursor (for example a silazane) is used, thepredicted composition would be Si_(w*)N_(x*)C_(y*)H_(z*), i.e. inSi_(w)O_(x)C_(y)H_(z) or its equivalent SiO_(x)C_(y) as specified in theDefinition Section, O is replaced by N and the indices for H are adaptedto the higher valency of N as compared to O (3 instead of 2. The latteradaptation will generally follow the ratio of w, x, y and z in aSiloxane to the corresponding indices in its aza counterpart. In aparticular aspect of the invention, Si_(w).N_(x).C_(y).H_(z). (or itsequivalent SiN_(X)*C_(y)*) in which w*, x*, y*, and z* are defined thesame as w, x, y, and z for the siloxane counterparts, but for anoptional deviation in the number of hydrogen atoms.

One type of precursor starting material having the above empiricalformula is a linear siloxane, for example a material having thefollowing formula:

in which each R is independently selected from alkyl, for examplemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl,alkyne, or others, and n is 1, 2, 3, 4, or greater, optionally two orgreater. Several examples of contemplated linear siloxanes arehexamethyldisiloxane (HMDSO),octamethyltrisiloxane,decamethyltetrasiloxane,dodecamethylpentasiloxane,or combinations of two or more of these. The analogous silazanes inwhich —NH— is substituted for the oxygen atom in the above structure arealso useful for making analogous pH protective coating or layers orcoating or layers. Several examples of contemplated linear silazanes areoctamethyltrisilazane, decamethyltetrasilazane, or combinations of twoor more of these.

Another type of precursor starting material, among the preferredstarting materials in the present context, is a monocyclic siloxane, forexample a material having the following structural formula:

in which R is defined as for the linear structure and “a” is from 3 toabout 10, or the analogous monocyclic silazanes. Several examples ofcontemplated hetero-substituted and unsubstituted monocyclic siloxanesand silazanes include1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,pentamethylcyclopentasiloxane,pentavinylpentamethylcyclopentasiloxane,hexamethylcyclotrisiloxane,hexaphenylcyclotrisiloxane,octamethylcyclotetrasiloxane (OMCTS),octaphenylcyclotetrasiloxane,decamethylcyclopentasiloxanedodecamethylcyclohexasiloxane,methyl(3,3,3-trifluoropropl)cyclosiloxane,Cyclic organosilazanes are also contemplated, such as

Octamethylcyclotetrasilazane,

1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasilazanehexamethylcyclotrisilazane,octamethylcyclotetrasilazane,decamethylcyclopentasilazane,dodecamethylcyclohexasilazane, orcombinations of any two or more of these.

Another type of precursor starting material, among the preferredstarting materials in the present context, is a polycyclic siloxane, forexample a material having one of the following structural formulas:

in which Y can be oxygen or nitrogen, E is silicon, and Z is a hydrogenatom or an organic substituent, for example alkyl such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others.When each Y is oxygen, the respective structures, from left to right,are a Silatrane, a Silquasilatrane, and a Silproatrane. When Y isnitrogen, the respective structures are an azasilatrane, anazasilquasiatrane, and an azasilproatrane.

Another type of polycyclic siloxane precursor starting material, amongthe preferred starting materials in the present context, is apolysilsesquioxane, with the empirical formula RSiO_(1.5) and thestructural formula:

in which each R is a hydrogen atom or an organic substituent, forexample alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, vinyl, alkyne, or others. Two commercial materials of this sortare SST-eM01 poly(methylsilsesquioxane), in which each R is methyl, andSST-3 MH1.1 poly(Methyl-Hydridosilsesquioxane), in which 90% of the Rgroups are methyl, 10% are hydrogen atoms. This material is available ina 10% solution in tetrahydrofuran, for example. Combinations of two ormore of these are also contemplated. Other examples of a contemplatedprecursor are methylsilatrane, CAS No. 2288-13-3, in which each Y isoxygen and Z is methyl, methylazasilatrane, poly(methylsilsesquioxane)(for example SST-eM01 poly(methylsilsesquioxane)), in which each Roptionally can be methyl, SST-3 MH1.1 poly(Methyl-Hydridosilsesquioxane)(for example SST-3 MH1.1 poly(Methyl-Hydridosilsesquioxane)), in which90% of the R groups are methyl and 10% are hydrogen atoms, or acombination of any two or more of these.

The analogous polysilsesquiazanes in which —NH— is substituted for theoxygen atom in the above structure are also useful for making analogouspH protective coating or layer. Examples of contemplatedpolysilsesquiazanes are a poly(methylsilsesquiazane), in which each R ismethyl, and a poly(Methyl-Hydridosilsesquiazane, in which 90% of the Rgroups are methyl, 10% are hydrogen atoms. Combinations of two or moreof these are also contemplated.

One particularly contemplated precursor for the barrier coating or layeraccording to the present invention is a linear siloxane, for example isHMDSO. One particularly contemplated precursor for the pH protectivecoating or layer and the pH protective coating or layer according to thepresent invention is a cyclic siloxane, for exampleoctamethylcyclotetrasiloxane (OMCTS).

It is believed that the OMCTS or other cyclic siloxane molecule providesseveral advantages over other siloxane materials. First, its ringstructure results in a less dense pH protective coating or layer (ascompared to pH protective coating or layer prepared from HMDSO). Themolecule also allows selective ionization so that the final structureand chemical composition of the pH protective coating or layer can bedirectly controlled through the application of the plasma power. Otherorganosilicon molecules are readily ionized (fractured) so that it ismore difficult to retain the original structure of the molecule.

In any of the PECVD methods according to the present invention, theapplying step optionally can be carried out by vaporizing the precursorand providing it in the vicinity of the substrate. For example, OMCTS isusually vaporized by heating it to about 50° C. before applying it tothe PECVD apparatus.

Cyclic organosilicon precursors, in particular monocyclic organosiliconprecursors (like the monocyclic precursors listed elsewhere in presentdescription), and specifically OMCTS, are particularly suitable toachieve a pH protective coating or layer.

Other Components of PECVD Reaction Mixture and Ratios of Components ForpH Protective Coating or Layer

Generally, for a pH protective coating or layer, O₂ can be present in anamount (which can, for example be expressed by the flow rate in sccm)which is less than one order of magnitude greater than the organosiliconamount. In contrast, in order to achieve a barrier coating or layer, theamount of O₂ typically is at least one order of magnitude higher thanthe amount of organosilicon precursor. In particular, the volume ratio(in sccm) of organosilicon precursor to O₂ for a pH protective coatingor layer can be in the range from 0.1:1 to 10:1, optionally in the rangefrom 0.3:1 to 8:1, optionally in the range from 0.5:1 to 5:1, optionallyfrom 1:1 to 3:1. The presence of the precursor and O₂ in the volumeratios as given in Tables 9-11 is specifically suitable to achieve a pHprotective coating or layer.

In one aspect of the invention, a carrier gas is absent in the reactionmixture, in another aspect of the invention, it is present. Suitablecarrier gases include Argon, Helium and other noble gases such as Neonand Xenon. When the carrier gas is present in the reaction mixture, itis typically present in a volume (in sccm) exceeding the volume of theorganosilicon precursor. For example, the ratio of the organosiliconprecursor to carrier gas can be from 1:1 to 1:50, optionally from 1:5 to1:40, optionally from 1:10 to 1:30. One function of the carrier gas isto dilute the reactants in the plasma, encouraging the formation of acoating or layer on the substrate instead of powdered reaction productsthat do not adhere to the substrate and are largely removed with theexhaust gases.

Since the addition of Argon gas improves the pH protective performance(see the working examples below), it is believed that additionalionization of the molecule in the presence of Argon contributes toproviding lubricity. The Si—O—Si bonds of the molecule have a high bondenergy followed by the Si—C, with the C—H bonds being the weakest. pHprotective appears to be achieved when a portion of the C—H bonds arebroken. This allows the connecting (cross-linking) of the structure asit grows. Addition of oxygen (with the Argon) is understood to enhancethis process. A small amount of oxygen can also provide C—O bonding towhich other molecules can bond. The combination of breaking C—H bondsand adding oxygen all at low pressure and power leads to a chemicalstructure that is solid while providing lubricity.

In any of embodiments, one preferred combination of process gasesincludes octamethylcyclotetrasiloxane (OMCTS) or another cyclic siloxaneas the precursor, in the presence of oxygen as an oxidizing gas andargon as a carrier gas. Without being bound to the accuracy of thistheory, the inventors believe this particular combination is effectivefor the following reasons. The presence of O₂, N₂O, or another oxidizinggas and/or of a carrier gas, in particular of a carrier gas, for examplea noble gas, for example Argon (Ar), is contemplated to improve theresulting pH protective coating or layer.

Some non-exhaustive alternative selections and suitable proportions ofthe precursor gas, oxygen, and a carrier gas are provided below.

OMCTS: 0.5-5.0 sccm

Oxygen: 0.1-5.0 sccm

Argon: 1.0-20 sccm

PECVD Apparatus for Forming pH Protective Coating or Layer

The low-pressure PECVD process described in U.S. Pat. No. 7,985,188 canbe used to provide the barrier, lubricity, and pH protective coating orlayers described in this specification. A brief synopsis of that processfollows, with reference to present FIGS. 4-6.

A PECVD apparatus suitable for performing the present invention includesa vessel holder 50, an inner electrode defined by the probe 108, anouter electrode 160, and a power supply 162. The pre-assembly 12 seatedon the vessel holder 50 defines a plasma reaction chamber, whichoptionally can be a vacuum chamber. Optionally, a source of vacuum 98, areactant gas source 144, a gas feed (probe 108) or a combination of twoor more of these can be supplied.

The PECVD apparatus can be used for atmospheric-pressure PECVD, in whichcase the plasma reaction chamber defined by the pre-assembly 12 does notneed to function as a vacuum chamber.

Referring to FIGS. 4-6, the vessel holder 50 comprises a gas inlet port104 for conveying a gas into the pre-assembly 12 seated on the opening82. The gas inlet port 104 has a sliding seal provided for example by atleast one O-ring 106, or two O-rings in series, or three O-rings inseries, which can seat against a cylindrical probe 108 when the probe108 is inserted through the gas inlet port 104. The probe 108 can be agas inlet conduit that extends to a gas delivery port at its distal end110. The distal end 110 of the illustrated embodiment can be inserteddeep into the pre-assembly 12 for providing one or more PECVD reactantsand other precursor feed or process gases.

FIG. 6 shows additional optional details of the coating station 60 thatare usable, for example, with all the illustrated embodiments. Thecoating station 60 can also have a main vacuum valve 574 in its vacuumline 576 leading to the pressure sensor 152. A manual bypass valve 578is provided in the bypass line 580. A vent valve 582 controls flow atthe vent 404.

Flow out of the PECVD gas or precursor source 144 is controlled by amain reactant gas valve 584 regulating flow through the main reactantfeed line 586. One component of the gas source 144 is the organosiliconliquid reservoir 588. The contents of the reservoir 588 are drawnthrough the organosilicon capillary line 590, which is provided at asuitable length to provide the desired flow rate. Flow of organosiliconvapor is controlled by the organosilicon shut-off valve 592. Pressure isapplied to the headspace 614 of the liquid reservoir 588, for example apressure in the range of 0-15 psi (0 to 78 cm. Hg), from a pressuresource 616 such as pressurized air connected to the headspace 614 by apressure line 618 to establish repeatable organosilicon liquid deliverythat is not dependent on atmospheric pressure (and the fluctuationstherein). The reservoir 588 is sealed and the capillary connection 620is at the bottom of the reservoir 588 to ensure that only neatorganosilicon liquid (not the pressurized gas from the headspace 614flows through the capillary tube 590. The organosilicon liquidoptionally can be heated above ambient temperature, if necessary ordesirable to cause the organosilicon liquid to evaporate, forming anorganosilicon vapor. To accomplish this heating, the pH protectivecoating or layer apparatus can advantageously include heated deliverylines from the exit of the precursor reservoir to as close as possibleto the gas inlet into the syringe. Preheating is useful, for example,when feeding OMCTS.

Oxygen is provided from the oxygen tank 594 via an oxygen feed line 596controlled by a mass flow controller 598 and provided with an oxygenshut-off valve 600.

Optionally in any embodiment, other precursor, reactant, and/or carriergas reservoirs such as 602 can be provided to supply additionalmaterials if needed for a particular deposition process. Each suchreservoir such as 602 has the appropriate feed line 604 and shut-offvalve 606.

Referring especially to FIG. 4, the processing station 28 can include anelectrode 160 fed by a radio frequency power supply 162 for providing anelectric field for generating plasma within the pre-assembly 12 duringprocessing. In this embodiment, the probe 108 is also electricallyconductive and is grounded, thus providing a counter-electrode withinthe pre-assembly 12. Alternatively, in any embodiment the outerelectrode 160 can be grounded and the probe 108 directly connected tothe power supply 162.

In the embodiment of FIGS. 4-6, the outer electrode 160 can either begenerally cylindrical as illustrated in FIGS. 4 and 5 or a generallyU-shaped elongated channel as illustrated in FIG. 6 (FIG. 5 being anembodiment of the section taken along section line A-A of FIG. 4). Eachillustrated embodiment has one or more sidewalls, such as 164 and 166,and optionally a top end 168, disposed about the pre-assembly 12 inclose proximity.

Specific PECVD conditions for application of a pH protective coating orlayer are provided below.

Plasma Conditions for pH Protective Coating or Layer

Typically, the plasma in the PECVD process is generated at RF frequency.For providing a pH protective coating or layer on the interior of avessel by a plasma reaction carried out within the vessel, the plasma ofany embodiment can be generated with an electric power of from 0.1 to500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W,optionally from 1 to 250 W, optionally from 1 to 200 W, even optionallyfrom 10 to 150 W, optionally from 20 to 150 W, for example of 40 W,optionally from 40 to 150 W, even optionally from 60 to 150 W. The ratioof the electrode power to the plasma volume can be less than 100 W/ml,optionally is from 5 W/ml to 75 W/ml, optionally is from 6 W/ml to 60W/ml, optionally is from 10 W/ml to 50 W/ml, optionally from 20 W/ml to40 W/ml. These power levels are suitable for applying pH protectivecoating or layers or coating or layers to syringes and cartridges andsample tubes and pharmaceutical packages or other vessels of similargeometry having a void volume of 5 mL in which PECVD plasma isgenerated. It is contemplated that for larger or smaller objects thepower applied, in Watts, should be increased or reduced accordingly toscale the process to the size of the substrate.

Exemplary reaction conditions for preparing a pH protective coating orlayer according to the present invention in a 3 ml sample size syringewith a ⅛″ diameter tube (open at the end) are as follows:

Flow Rate Ranges:

OMCTS: 0.5-10 sccm

Oxygen: 0.1-10 sccm

Argon: 1.0-200 sccm

Power: 0.1-500 watts

Specific Flow Rates:

OMCTS: 2.0 sccm

Oxygen: 0.7 sccm

Argon: 7.0 sccm

Power: 3.5 watts

The pH protective coating or layer and its application are described inmore detail below. A method for applying the coating or layer includesseveral steps. A vessel wall is provided, as is a reaction mixturecomprising plasma forming gas, i.e. an organosilicon compound gas,optionally an oxidizing gas, and optionally a hydrocarbon gas.

Plasma is formed in the reaction mixture that is substantially free ofhollow cathode plasma. The vessel wall is contacted with the reactionmixture, and the pH protective coating or layer of SiO_(x) is depositedon at least a portion of the vessel wall.

In certain embodiments, the generation of a uniform plasma throughoutthe portion of the vessel to be coated is contemplated, as it has beenfound in certain instances to generate a better pH protective coating orlayer. Uniform plasma means regular plasma that does not include asubstantial amount of hollow cathode plasma (which has a higher emissionintensity than regular plasma and is manifested as a localized area ofhigher intensity interrupting the more uniform intensity of the regularplasma).

Container Closure Integrity

Optionally in any embodiment, the container closure integrity of thecapped pre-assembly can be measured before, during, or after theapplication of a vapor-deposited coating or layer.

A container closure integrity (CCI) test is a non-destructive leak testmethod intended for use in manufacturing as an in-process packageintegrity check. A CCI test is intended to determine the microbialbarrier properties of a sterile container indirectly, as by measuring aphysical property that is correlated with microbial barrier properties.Respecting the present capped pre-assemblies, the CCI test is apreliminary test that determines the package integrity of the front endof the syringe, in particular the barrel, dispensing portion, and cap.This CCI test can be carried out on the unfilled but capped pre-assemblyto determine whether these components of the package have theappropriate barrier properties.

Since in the present method the dispensing portion and cap are alreadypresent and installed when the barrier coatings are applied to thebarrel, the container closure integrity of the pre-assembly can beverified to assure, before the capped pre-assembly is filled with anexpensive pharmaceutical preparation, that these components do not haveany defects that would cause the filled package to be rejected.

Moreover, the test optionally can be carried out using the sameequipment commonly used for many vapor deposition processes, inparticular a vacuum arrangement to draw a vacuum on the syringe barreland associated dispensing portion and cap, which can be combined withleak detection equipment as shown in the first working example below.Thus, the CCI test can be carried out quickly, which is very importantto allow the test to be carried out on each package as it ismanufactured.

Example 1 below shows a CCI test conducted on the pre-assembly in 20seconds. More broadly, it is contemplated for any embodiment that thepresent CCI test can be carried out in a time between 1 second and 60seconds, alternatively between 2 seconds and 60 seconds, alternativelybetween 3 seconds and 60 seconds, alternatively between 4 seconds and 60seconds, alternatively between 5 seconds and 60 seconds, alternativelybetween 6 seconds and 60 seconds, alternatively between 7 seconds and 60seconds, alternatively between 8 seconds and 60 seconds, alternativelybetween 9 seconds and 60 seconds, alternatively between 10 seconds and60 seconds, alternatively between 11 second and 60 seconds,alternatively between 12 seconds and 60 seconds, alternatively between13 seconds and 60 seconds, alternatively between 14 seconds and 60seconds, alternatively between 15 seconds and 60 seconds, alternativelybetween 16 seconds and 60 seconds, alternatively between 17 seconds and60 seconds, alternatively between 18 seconds and 60 seconds,alternatively between 19 seconds and 60 seconds, alternatively between 1second and 20 seconds, alternatively between 2 seconds and 20 seconds,alternatively between 3 seconds and 20 seconds, alternatively between 4seconds and 20 seconds, alternatively between 5 seconds and 20 seconds,alternatively between 6 seconds and 20 seconds, alternatively between 7seconds and 20 seconds, alternatively between 8 seconds and 20 seconds,alternatively between 9 seconds and 20 seconds, alternatively between 10seconds and 20 seconds, alternatively between 11 seconds and 20 seconds,alternatively between 12 seconds and 20 seconds, alternatively between13 seconds and 20 seconds, alternatively between 14 seconds and 20seconds, alternatively between 15 seconds and 20 seconds, alternativelybetween 16 seconds and 20 seconds, alternatively between 17 seconds and20 seconds, alternatively between 18 seconds and 20 seconds,alternatively between 19 seconds and 20 seconds, alternatively between20 seconds and 60 seconds, alternatively between 10 seconds and 50seconds, alternatively between 10 seconds and 40 seconds, alternativelybetween 10 seconds and 30 seconds, alternatively between 10 seconds and20 seconds, alternatively between 20 seconds and 50 seconds,alternatively between 20 seconds and 40 seconds, alternatively between20 seconds and 30 seconds.

In any embodiment, the CCI test can be carried out, while drawing atleast a partial vacuum through the barrel opening (32), by measuring thepressure decay of gas drawn from the barrel opening (32) and any leakagepaths.

In any embodiment, the CCI test can be carried out by comparing thepressure decay of gas to a predetermined standard to determine thecontainer closure integrity of the capped pre-assembly.

In any embodiment, the pressure decay can be measured with sufficientprecision to detect a pressure decay due to an intact container versus acontainer having a single perforation in the cap having a diameter of 5microns, alternatively 4 microns, alternatively 3 microns, alternatively2 microns, alternatively 1.8 microns, alternatively 1 micron,alternatively 0.5 microns, alternatively 0.3 microns, alternatively 0.1microns.

In any embodiment, the pressure decay can be measured within a timebetween 1 second and 60 seconds, alternatively between 2 seconds and 60seconds, alternatively between 3 seconds and 60 seconds, alternativelybetween 4 seconds and 60 seconds, alternatively between 5 seconds and 60seconds, alternatively between 6 seconds and 60 seconds, alternativelybetween 7 seconds and 60 seconds, alternatively between 8 seconds and 60seconds, alternatively between 9 seconds and 60 seconds, alternativelybetween 10 seconds and 60 seconds, alternatively between 11 seconds and60 seconds, alternatively between 12 seconds and 60 seconds,alternatively between 13 seconds and 60 seconds, alternatively between14 seconds and 60 seconds, alternatively between 15 seconds and 60seconds, alternatively between 16 seconds and 60 seconds, alternativelybetween 17 seconds and 60 seconds, alternatively between 18 seconds and60 seconds, alternatively between 19 seconds and 60 seconds,alternatively between 20 seconds and 60 seconds, alternatively between10 seconds and 50 seconds, alternatively between 10 seconds and 40seconds, alternatively between 10 seconds and 30 seconds, alternativelybetween 10 seconds and 20 seconds.

In any embodiment, the pressure decay of gas drawn from the barrelopening (32) and any leakage paths can be measured before applying avapor-deposited coating or layer.

In any embodiment, the pressure decay of gas drawn from the barrelopening (32) and any leakage paths can be measured while applying avapor-deposited coating or layer.

In any embodiment, the pressure decay of gas drawn from the barrelopening (32) and any leakage paths can be measured after applying avapor-deposited coating or layer.

Measurement of Coating or Layer Thickness

The thickness of a PECVD coating or layer such as the pH protectivecoating or layer, the barrier coating or layer, and/or a composite ofany two or more of these coatings or layers can be measured, forexample, by transmission electron microscopy (TEM). An exemplary TEMimage for a pH protective coating or layer is shown in FIG. 21. Anexemplary TEM image for an SiO₂ barrier coating or layer is shown inFIG. 22.

The TEM can be carried out, for example, as follows. Samples can beprepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Eitherthe samples can be first coated with a thin coating or layer of carbon(50-100 nm thick) and then coated with a sputtered coating or layer ofplatinum (50-100 nm thick) using a K575X Emitech pH protective coatingor layer system, or the samples can be coated directly with the pHprotective sputtered Pt coating or layer. The coated samples can beplaced in an FEI FIB200 FIB system. An additional coating or layer ofplatinum can be FIB-deposited by injection of an organometallic gaswhile rastering the 30 kV gallium ion beam over the area of interest.The area of interest for each sample can be chosen to be a location halfway down the length of the syringe barrel. Thin cross sections measuringapproximately 15 μm (“micrometers”) long, 2 μm wide and 15 μm deep canbe extracted from the die surface using an in-situ FIB lift-outtechnique. The cross sections can be attached to a 200 mesh copper TEMgrid using FIB-deposited platinum. One or two windows in each section,measuring about 8 μm wide, can be thinned to electron transparency usingthe gallium ion beam of the FEI FIB.

Cross-sectional image analysis of the prepared samples can be performedutilizing either a Transmission Electron Microscope (TEM), or a ScanningTransmission Electron Microscope (STEM), or both. All imaging data canbe recorded digitally. For STEM imaging, the grid with the thinned foilscan be transferred to a Hitachi HD2300 dedicated STEM. Scanningtransmitted electron images can be acquired at appropriatemagnifications in atomic number contrast mode (ZC) and transmittedelectron mode (TE). The following instrument settings can be used.

Scanning Transmission Instrument Electron Microscope Manufacturer/ModelHitachi HD2300 Accelerating Voltage 200 kV Objective Aperture #2Condenser Lens 1 Setting 1.672 Condenser Lens 2 Setting 1.747Approximate Objective Lens Setting 5.86 ZC Mode Projector Lens 1.149 TEMode Projector Lens 0.7 Image Acquisition Pixel Resolution 1280 × 960Acquisition Time 20 sec.(x4

For TEM analysis the sample grids can be transferred to a Hitachi HF2000transmission electron microscope. Transmitted electron images can beacquired at appropriate magnifications. The relevant instrument settingsused during image acquisition can be those given below.

Instrument Transmission Electron Microscope Manufacturer/Model HitachiHF2000 Accelerating Voltage 200 kV Condenser Lens 1 0.78 Condenser Lens2 0 Objective Lens 6.34 Condenser Lens Aperture #1 Objective LensAperture for imaging #3 Selective Area Aperture for SAD N/A

Any of the above methods can also include as a step forming a coating orlayer on the exterior outer wall of a pre-assembly 12. The exteriorcoating or layer optionally can be a barrier coating or layer,optionally an oxygen barrier coating or layer, or optionally a waterbarrier coating or layer. The exterior coating or layer can also be anarmor coating or layer that protects the outer wall of a pre-assembly12. One example of a suitable exterior coating or layer ispolyvinylidene chloride, which functions both as a water barrier and anoxygen barrier. Optionally, the exterior coating or layer can be appliedas a water-based coating or layer. The exterior coating or layeroptionally can be applied by dipping the vessel in it, spraying it onthe pharmaceutical package or other vessel, or other expedients.

PECVD Treated Pharmaceutical Packages or Other Vessels CoatedPharmaceutical Packages or Other Vessels

Pharmaceutical packages 210 or other vessels, such as a prefilledsyringe (schematically shown in FIG. 7) or cartridge are contemplatedhaving a barrier coating or layer such as 30 at least partially coveredby a pH protective coating or layer such as 34.

The pharmaceutical package 210 as shown in any embodiment, for exampleFIG. 7, comprises a pre-assembly 12; optionally a barrier coating orlayer such as 30 on the vessel or vessel part; a pH protective coatingor layer such as 34 on the vessel, vessel part, or barrier coating orlayer; and a pharmaceutical composition or other fluid material 40contained within the vessel.

The barrier coating or layer such as 30 can be an SiO_(x) barriercoating or layer applied as described in any embodiment of thisspecification or in U.S. Pat. No. 7,985,188. For example, the barriercoating or layer such as 30 of any embodiment can be applied at athickness of at least 2 nm, or at least 4 nm, or at least 7 nm, or atleast 10 nm, or at least 20 nm, or at least 30 nm, or at least 40 nm, orat least 50 nm, or at least 100 nm, or at least 150 nm, or at least 200nm, or at least 300 nm, or at least 400 nm, or at least 500 nm, or atleast 600 nm, or at least 700 nm, or at least 800 nm, or at least 900nm. The barrier coating or layer can be up to 1000 nm, or at most 900nm, or at most 800 nm, or at most 700 nm, or at most 600 nm, or at most500 nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or atmost 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm, or atmost 60 nm, or at most 50 nm, or at most 40 nm, or at most 30 nm, or atmost 20 nm, or at most 10 nm, or at most 5 nm thick. Specific thicknessranges composed of any one of the minimum thicknesses expressed above,plus any equal or greater one of the maximum thicknesses expressedabove, are expressly contemplated. The thickness of the SiO_(x) or otherbarrier coating or layer can be measured, for example, by transmissionelectron microscopy (TEM), and its composition can be measured by X-rayphotoelectron spectroscopy (XPS). The pH protective coating or layerdescribed herein can be applied to a variety of pharmaceutical packagesor other vessels made from plastic or glass, for example to plastictubes, vials, and syringes and cartridges.

The pH protective coating or layer such as 34 can be an SiO_(x)C_(y) pHprotective coating or layer applied as described in any embodiment ofthis specification. For example, the vapor deposited coating or layer,here a pH protective coating or layer such as 34, comprises or consistsessentially of a coating or layer of SiO_(x)C_(y) applied over thebarrier coating or layer 30 to protect at least a portion of the barriercoating or layer from the pharmaceutical preparation such as 40 in FIG.7. The pH protective coating or layer such as 34 is provided, forexample, by applying one of the described precursors on or in thevicinity of a substrate in a PECVD process, providing a pH protectivecoating or layer. The coating or layer can be applied, for example, at athickness of 1 to 5000 nm, or 10 to 1000 nm, or 10 to 500 nm, or 10 to200 nm, or 20 to 100 nm, or 30 to 1000 nm, or 30 to 500 nm thick, or 30to 1000 nm, or 20 to 100 nm, or 80 to 150 nm, and crosslinking orpolymerizing (or both) the pH protective coating or layer, optionally ina PECVD process, to provide a protected surface.

Although not intending to be bound according to the accuracy of thefollowing theory, the inventors contemplate that the pH protectivecoating or layer, applied over an SiO_(x) barrier coating or layer on avessel wall, functions at least in part by passivating the SiO_(x)barrier coating or layer surface against attack by the contents of thevessel, as well as providing a more resistant or sacrificial independentcoating or layer to isolate the SiO_(x) barrier coating or layer fromthe contents of the vessel. It is thus contemplated that the pHprotective coating or layer can be very thin, and even so improve theshelf life of the pharmaceutical package.

Another expedient contemplated here, for adjacent coating or layers ofSiO_(x) and a pH protective coating or layer, is a graded composite ofSiO_(x) and Si_(w)O_(x)C_(y), or its equivalent SiO_(x)C_(y), as definedin the Definition Section. A graded composite can be separate coating orlayers of a pH protective and/or barrier coating or layer or coating orlayer with a transition or interface of intermediate composition betweenthem, or separate coating or layers of a pH protective and/orhydrophobic coating or layer and SiO_(x) with an intermediate distinctpH protective coating or layer of intermediate composition between them,or a single coating or layer that changes continuously or in steps froma composition of a pH protective and/or hydrophobic coating or layer toa composition more like SiO_(x), going through the pH protective coatingor layer in a normal direction.

The grade in the graded composite can go in either direction. Forexample, the composition of SiO_(x) can be applied directly to thesubstrate and graduate to a composition further from the surface of a pHprotective coating or layer, and optionally can further graduate toanother type of coating or layer, such as a hydrophobic coating or layeror a pH protective coating or layer. Additionally, in any embodiment anadhesion coating or layer, for example Si_(w)O_(x)C_(y), or itsequivalent SiO_(x)C_(y), optionally can be applied directly to thesubstrate before applying the barrier coating or layer. A graduated pHprotective coating or layer is particularly contemplated if a coating orlayer of one composition is better for adhering to the substrate thananother, in which case the better-adhering composition can, for example,be applied directly to the substrate. It is contemplated that the moredistant portions of the graded pH protective coating or layer can beless compatible with the substrate than the adjacent portions of thegraded pH protective coating or layer, since at any point the pHprotective coating or layer is changing gradually in properties, soadjacent portions at nearly the same depth of the pH protective coatingor layer have nearly identical composition, and more widely physicallyseparated portions at substantially different depths can have morediverse properties. It is also contemplated that a pH protective coatingor layer portion that forms a better barrier against transfer ofmaterial to or from the substrate can be directly against the substrate,to prevent the more remote pH protective coating or layer portion thatforms a poorer barrier from being contaminated with the materialintended to be barred or impeded by the barrier.

The applied coating or layers or coating or layers, instead of beinggraded, optionally can have sharp transitions between one coating orlayer and the next, without a substantial gradient of composition. SuchpH protective coating or layer can be made, for example, by providingthe gases to produce a coating or layer as a steady state flow in anon-plasma state, then energizing the system with a brief plasmadischarge to form a coating or layer on the substrate. If a subsequentpH protective coating or layer is to be applied, the gases for theprevious pH protective coating or layer are cleared out and the gasesfor the next pH protective coating or layer are applied in asteady-state fashion before energizing the plasma and again forming adistinct coating or layer on the surface of the substrate or itsoutermost previous pH protective coating or layer, with little if anygradual transition at the interface.

Vessel Made Of Glass

Another embodiment is a pharmaceutical package 210 as shown in anyembodiment, for example FIG. 7, comprising a barrel 14 and/or piston 36and/or plunger rod 38 made of glass; optionally a barrier coating orlayer such as 30, a pH protective coating or layer 30 (if a sole layer)or 34 (if formed over a barrier layer) and a pharmaceutical compositionor preparation or other fluid material 40 contained within the vessel.In this embodiment a barrier coating or layer is optional because aglass vessel wall in itself is an extremely good barrier coating orlayer. It is contemplated to optionally provide a barrier coating orlayer primarily to provide isolation: in other words, to prevent contactand interchange of material of any kind, such as ions of the glass orconstituents of the pharmaceutical composition or preparation betweenthe vessel wall and the contents of the vessel. The pH protectivecoating or layer as defined in this specification is contemplated toperform the isolation function independently, at least to a degree. Thisprotection coating or layer is contemplated to provide a useful functionon glass in contact with the pharmaceutical composition or preparation,as the present working examples show that borosilicate glass, commonlyused today for pharmaceutical packaging, is dissolved by a fluidcomposition having a pH exceeding 5. Particularly in applications wheresuch dissolution is disadvantageous or perceived to be disadvantageous,the present pH protective coating or layers or coating or layers willfind utility.

The vessel can be made, for example of glass of any type used in medicalor laboratory applications, such as soda-lime glass, borosilicate glass,or other glass formulations. One function of a pH protective coating orlayer on a glass vessel can be to reduce the ingress of ions in theglass, either intentionally or as impurities, for example sodium,calcium, or others, from the glass to the contents of the pharmaceuticalpackage or other vessel, such as a reagent or blood in an evacuatedblood collection tube. Alternatively, a dual functional pH protective/pHprotective coating or layer can be used on a glass vessel in whole or inpart, such as selectively at surfaces contacted in sliding relation toother parts, to provide lubricity, for example to ease the insertion orremoval of a stopper or passage of a sliding element such as a piston ina syringe, as well as to provide the isolation of a pH protectivecoating or layer. Still another reason to coat a glass vessel, forexample with a dual functional hydrophobic and pH protective coating orlayer, is to prevent a reagent or intended sample for the pharmaceuticalpackage or other vessel, such as blood, from sticking to the wall of thevessel or an increase in the rate of coagulation of the blood in contactwith the wall of the vessel, as well as to provide the isolation of a pHprotective coating or layer.

A related embodiment is a barrel 14 of a syringe, cartridge, or the likeas described in the previous paragraphs, in which the barrier coating orlayer is made of soda lime glass, borosilicate glass, or another type ofglass coating or layer on a substrate.

II. Gaseous Reactant or Process Gas Limitations of any EmbodimentDeposition Conditions of any Embodiment

The plasma for PECVD, if used, can be generated at reduced pressure andthe reduced pressure can be less than 300 mTorr, optionally less than200 mTorr, even optionally less than 100 mTorr. The physical andchemical properties of the pH protective coating or layer can be set bysetting the ratio of O₂ to the organosilicon precursor in the gaseousreactant, and/or by setting the electric power used for generating theplasma.

Relative Proportions of Gases of any Embodiment

The process gas can contain this ratio of gases for preparing a pHprotective coating or layer:

-   -   from 0.5 to 10 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.1 to 10 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 80 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes, of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 1 to 100 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   2 to 4 standard volumes, of the precursor;    -   from 3 to 70 standard volumes of a carrier gas,    -   from 0.2 to 1 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes    -   of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes, of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.1 to 2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes, of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes, of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.5 to 1.5 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 2 to 4 standard volumes of the precursor;    -   from 5 to 100 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   from 1 to 6 standard volumes of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.        alternatively this ratio:    -   2 to 4 standard volumes, of the precursor;    -   from 10 to 70 standard volumes of a carrier gas,    -   from 0.8 to 1.2 standard volumes of an oxidizing agent.

Carrier Gas of any Embodiment

The carrier gas can comprise or consist of an inert gas, for exampleargon, helium, xenon, neon, another gas that is inert to the otherconstituents of the process gas under the deposition conditions, or anycombination of two or more of these.

Oxidizing Gas of any Embodiment

The oxidizing gas can comprise or consist of oxygen (O₂ and/or O₃(commonly known as ozone)), nitrous oxide, or any other gas thatoxidizes the precursor during PECVD at the conditions employed. Theoxidizing gas comprises about 1 standard volume of oxygen. The gaseousreactant or process gas can be at least substantially free of nitrogen.

III. Plasma of any Embodiment

The plasma of any PECVD embodiment can be formed in the vicinity of thesubstrate. The plasma can in certain cases, especially when preparing abarrier coating or layer, be a non-hollow-cathode plasma. In othercertain cases, especially when preparing a pH protective coating orlayer, a non-hollow-cathode plasma is not desired. The plasma can beformed from the gaseous reactant at reduced pressure. Sufficient plasmageneration power input can be provided to induce pH protective coatingor layer formation on the substrate.

IV. RF Power of any Embodiment

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes powered at a frequency of 10kHz to 2.45 GHz, alternatively from about 13 to about 14 MHz.

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes powered at radio frequency,optionally at a frequency of from 10 kHz to less than 300 MHz,optionally from 1 to 50 MHz, even optionally from 10 to 15 MHz,optionally at 13.56 MHz.

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes supplied with electric powerat from 0.1 to 25 W, optionally from 1 to 22 W, optionally from 1 to 10W, even optionally from 1 to 5 W, optionally from 2 to 4 W, for exampleof 3 W, optionally from 3 to 17 W, even optionally from 5 to 14 W, forexample 6 or 7.5 W, optionally from 7 to 11 W, for example of 8 W, from0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300W, optionally from 1 to 250 W, optionally from 1 to 200 W, evenoptionally from 10 to 150 W, optionally from 20 to 150 W, for example of40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W.

The precursor can be contacted with a plasma made by energizing thevicinity of the precursor with electrodes supplied with electric powerdensity at less than 10 W/ml of plasma volume, alternatively from 6 W/mlto 0.1 W/ml of plasma volume, alternatively from 5 W/ml to 0.1 W/ml ofplasma volume, alternatively from 4 W/ml to 0.1 W/ml of plasma volume,alternatively from 2 W/ml to 0.2 W/ml of plasma volume, alternativelyfrom 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.

The plasma can be formed by exciting the reaction mixture withelectromagnetic energy, alternatively microwave energy.

V. Other Process Options of any Embodiment

The applying step for applying a pH protective coating or layer to thesubstrate can be carried out by vaporizing the precursor and providingit in the vicinity of the substrate.

The chemical vapor deposition employed can be PECVD and the depositiontime can be from 1 to 30 sec, alternatively from 2 to 10 sec,alternatively from 3 to 9 sec. The purposes for optionally limitingdeposition time can be to avoid overheating the substrate, to increasethe rate of production, and to reduce the use of process gas and itsconstituents. The purposes for optionally extending deposition time canbe to provide a thicker pH protective coating or layer for particulardeposition conditions.

VI. Protective Coating or Layer Properties of any Embodiment Thicknessof any Embodiment

Optionally, the pH protective coating or layer can have a thicknessdetermined by transmission electron microscopy (TEM), of any amountstated in this disclosure.

Composition of any Embodiment

Optionally, the pH protective coating or layer can be composed ofSi_(w)O_(x)C_(y)H_(z) (or its equivalent SiO_(x)C_(y)) orSi_(w)N_(x)C_(y)H_(z) or its equivalent SiN_(x)C_(y)), each as definedpreviously. The atomic ratio of Si:O:C can be determined by XPS (X-rayphotoelectron spectroscopy). Taking into account the H atoms, the pHprotective coating or layer may thus in one aspect have the formulaSi_(w)O_(x)C_(y)H_(z), or its equivalent SiO_(x)C_(y), for example wherew is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to about3, and z is from about 2 to about 9.

Typically, expressed as the formula Si_(w)O_(x)C_(y), the atomic ratiosof Si, O, and C are, as several options:

Si 100: O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);

Si 100: O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)

Si 100: O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to 1.5)

Si 100: O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to 1.4), or

Si 100: O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to 1.33).

Alternatively, the pH protective coating or layer can have atomicconcentrations normalized to 100% carbon, oxygen, and silicon, asdetermined by X-ray photoelectron spectroscopy (XPS) of less than 50%carbon and more than 25% silicon. Alternatively, the atomicconcentrations are from 25 to 45% carbon, 25 to 65% silicon, and 10 to35% oxygen. Alternatively, the atomic concentrations are from 30 to 40%carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively, theatomic concentrations are from 33 to 37% carbon, 37 to 47% silicon, and22 to 26% oxygen.

Optionally, the atomic concentration of carbon in the pH protectivecoating or layer, normalized to 100% of carbon, oxygen, and silicon, asdetermined by X-ray photoelectron spectroscopy (XPS), can be greaterthan the atomic concentration of carbon in the atomic formula for theorganosilicon precursor. For example, embodiments are contemplated inwhich the atomic concentration of carbon increases by from 1 to 80atomic percent, alternatively from 10 to 70 atomic percent,alternatively from 20 to 60 atomic percent, alternatively from 30 to 50atomic percent, alternatively from 35 to 45 atomic percent,alternatively from 37 to 41 atomic percent.

Optionally, the atomic ratio of carbon to oxygen in the pH protectivecoating or layer can be increased in comparison to the organosiliconprecursor, and/or the atomic ratio of oxygen to silicon can be decreasedin comparison to the organosilicon precursor.

Optionally, the pH protective coating or layer can have an atomicconcentration of silicon, normalized to 100% of carbon, oxygen, andsilicon, as determined by X-ray photoelectron spectroscopy (XPS), lessthan the atomic concentration of silicon in the atomic formula for thefeed gas. For example, embodiments are contemplated in which the atomicconcentration of silicon decreases by from 1 to 80 atomic percent,alternatively by from 10 to 70 atomic percent, alternatively by from 20to 60 atomic percent, alternatively by from 30 to 55 atomic percent,alternatively by from 40 to 50 atomic percent, alternatively by from 42to 46 atomic percent.

As another option, a pH protective coating or layer is contemplated thatcan be characterized by a sum formula wherein the atomic ratio C:O canbe increased and/or the atomic ratio Si:O can be decreased in comparisonto the sum formula of the organosilicon precursor.

Other pH Protective Coating or Layer Properties of any Embodiment

The pH protective coating or layer can have a density between 1.25 and1.65 g/cm³, alternatively between 1.35 and 1.55 g/cm³, alternativelybetween 1.4 and 1.5 g/cm³, alternatively between 1.4 and 1.5 g/cm³,alternatively between 1.44 and 1.48 g/cm³, as determined by X-rayreflectivity (XRR). Optionally, the organosilicon compound can beoctamethylcyclotetrasiloxane and the pH protective coating or layer canhave a density which can be higher than the density of a pH protectivecoating or layer made from HMDSO as the organosilicon compound under thesame PECVD reaction conditions.

The pH protective coating or layer optionally can prevent or reduce theprecipitation of a compound or component of a composition in contactwith the pH protective coating or layer, in particular can prevent orreduce insulin precipitation or blood clotting, in comparison to theuncoated surface and/or to a barrier coated surface using HMDSO asprecursor.

The substrate can be a pharmaceutical package or other vessel, forprotecting a compound or composition contained or received in the vesselwith a pH protective coating or layer against mechanical and/or chemicaleffects of the surface of the uncoated substrate.

The substrate can be a pharmaceutical package or other vessel, forpreventing or reducing precipitation and/or clotting of a compound or acomponent of the composition in contact with the inner or interiorsurface of the vessel. The compound or composition can be a biologicallyactive compound or composition, for example a medicament, for examplethe compound or composition can comprise insulin, wherein insulinprecipitation can be reduced or prevented. Alternatively, the compoundor composition can be a biological fluid, for example a bodily fluid,for example blood or a blood fraction wherein blood clotting can bereduced or prevented.

The pH protective coating or layer optionally can have an RMS surfaceroughness value (measured by AFM) of from about 5 to about 9, optionallyfrom about 6 to about 8, optionally from about 6.4 to about 7.8. TheR_(a) surface roughness value of the pH protective coating or layer,measured by AFM, can be from about 4 to about 6, optionally from about4.6 to about 5.8. The R_(max) surface roughness value of the pHprotective coating or layer, measured by AFM, can be from about 70 toabout 160, optionally from about 84 to about 142, optionally from about90 to about 130.

VII. Product Made of Vessel Plus Contents, Optional for any Embodiment

In any embodiment, the substrate can be a vessel having an inner orinterior surface defining a lumen and an exterior surface, the pHprotective coating or layer can be on the inner or interior surface ofthe pharmaceutical package or other vessel, and the vessel can contain acompound or composition in its lumen, for example citrate or a citratecontaining composition, or for example insulin or an insulin containingcomposition. A prefilled syringe or cartridge is especially consideredwhich contains injectable or other liquid drugs like insulin.

Optionally for any of the embodiments, illustrated for example in FIG.7, the capped pre-assembly of the Figures can be filled with a fluidmaterial 40. Examples of a suitable fluid composition are any one or acombination of any two or more members selected from the group recitedin the claims.

As several examples, the fluid material 40 can be an inhalationanesthetic, a drug, or a diagnostic test material. Any of these fluidmaterials 40 can be an injectable material, a volatile material capableof being inhaled, or otherwise capable of being introduced into asubject.

EXAMPLE 1 Container Closure Integrity

A test was performed using as samples commercially obtained cappedpre-assemblies with staked needles (1 ml. capacity “long” style syringeswithout plungers) similar to those of the present FIGS. 1-5. The caps 28were made of elastomeric material. Thus, the seated caps 28 of thepre-assemblies 12 isolated the distal openings 24 due to contact betweenthe caps 28 and the barrels 14.

A test group of ten pre-assemblies was used as supplied, with intactcaps 28. A control group of five pre-assemblies (“perforated caps”) wasmodified by intentionally providing one round aperture of controlleddiameter through the wall of each cap 28. The apertures of controlleddiameter were made by pushing one fused silica glass capillary of knowninside diameter (2 microns) through each cap. The capillaries wereinserted from inside the barrel lumen 18 out through the hypodermicneedle distal opening 24 and through the end of the needle cap 28. Thecapillaries thus bypassed the seals created by the ribs 42 (per FIG. 3),as well as the seals created by burying the dispensing portions 20 inthe material of the caps 28. The capillaries were then cut at both endsto ensure that the capillaries were not clogged. It is believed that theoutside walls of the silica glass capillaries were essentially sealedagainst the material of the needle cap, thus effectively limitingleakage to flow through the internal passages of the capillaries ofknown internal diameter and round cross-section. This test primarilyevaluated the ability of the cap 28 to prevent leakage of material fromthe barrel lumen.

The test was conducted using an ATC (Advanced Test Concepts, Inc.) LeakTek mass flow leak detector. The flange end or opening 32 of eachpre-assembly was sealed on a test fixture comprising a seat with anO-ring seal connected in series via the conical flow cell of the ATCmass flow leak detector to a vacuum pump, with a side passage 386provided to bypass the ATC machine when initially pumping down thebarrel lumen 18 from ambient pressure. This test set-up is illustratedschematically in FIG. 30 of U.S. Pat. No. 7,985,188, with thepre-assembly 12 serving as the vessel 358.

The following testing conditions were used for test runs. A pre-assembly12 was clamped against the O-ring of the test fixture using a clampingpressure of 40 psi to seat the pre-assembly on the test fixture. Then,the vacuum pump was operated for 5 sec. with the side passage 386 opento pump down the barrel lumen 18 to its initial vacuum. The side passage386 was closed at an elapsed time set equal to zero seconds while thevacuum pump remained in operation to induce flow through the ATCmachine. The test was started at an elapsed time of one second bymeasuring the vacuum level a first time as reported in the tables belowin millibars, using the ATC machine. At an elapsed time of 21 seconds,providing a total test time of 20 sec., the test was concluded bymeasuring the vacuum level a second time as reported in the tables belowin millibars, using the ATC machine. The difference between the 1^(st)and 2^(nd) measurements was determined for each test, reported in Tables1 and 2, and plotted in FIG. 8 as pressure decay.

Referring to Table 1 and plot 52 presenting the data for the intactcaps, the average pressure decay (in this case, more precisely, vacuumdecay) was 4.8 millibars, with a maximum decay of 5.1 millibars and astandard deviation of 0.2 millibars. This maximum decay was used as astandard against which to measure the effect of introducing aperturesinto the intact caps.

Referring to Table 2 and plot 54 presenting the data for the perforatedcaps, the average pressure decay was 13.5 millibars, with a minimumdecay of 11.6 millibars and a standard deviation of 2.4 millibars. Sincethe perforated caps clearly had a statistically significant, higherpressure decay than the intact caps, the two were easily distinguishedin a 20-second test.

The pressure decay is believed to have occurred (although the inventionis not limited according to the accuracy of this theory) because theinitial pressure was measured after a brief period of time (one second)to allow the unit to reach a quasi-steady state. At this time, the massflow had the indicated baseline value, believed to be related to theamount of mass extracted from the surface of container. When there was ahole in the container, by the second measurement time ambient atmosphereoutside the container was pulled into the container by the vacuum,creating a larger mass flow. The amount of mass flow was related to thesize of the hole. By this means a non-integral container was easilydetected because it had a greater pressure decay than a predeterminedstandard (in this case, the standard was established by the tests onintact caps).

This method used sensitive pressure transducers to measure a pressuredifferential, which optionally can be converted to a mass flow rate. Themass flow rate was determined very quickly after a few seconds ofdrawing a vacuum on the container to be tested. This method is amenableto high speed, on-line, high sensitivity container closure integrity(CCI) testing. In every case the mass flow detector was off scale whencapillaries down to 1.8 microns ID were tested. This indicates that thetest can be carried out more quickly and/or with smaller capillariesthan those used in this test.

A second container closure integrity test can be conducted, in which thecaps 28 are perforated between the rib 42 and the portion of the cap 28in contact with the dispensing portion 20. This test provides a failurebypassing just the seal created by the rib 42, thus testing the abilityof the caps 28 to prevent contamination of the outside of the needle orother dispensing portion 20. Using both the former and the latter tests,one can completely test the container closure integrity of the seal.

EXAMPLE 2 Deposition of Coating Products in Dispensing Portion Lumen 26

The following example was carried out as described below, and shows thatthere was no significant increase in Si on the syringe needle based onthe PECVD coating process. This example demonstrates that the interiorportion of the needle did not get significantly coated during the PECVDcoating process, if coated with the needle cap applied.

Two studies were untaken with 100 needles in each study.

In the first study, 96 staked-needle 1 ml capacity long style syringes,which were only coated with a barrier coating or layer 30, and 100uncoated but otherwise similar syringes were obtained. The needles wereremoved from syringes by heating the plastic needle hub and needle witha flame, then pulling the needle from the syringe with tweezers. Carewas taken to secure the needle with the tweezers immediately next to theplastic hub. This ensured that if the needle was collapsed by thetweezers, the collapsed area was in the middle of the needle and bothends remained open to allow solution to access the needle. The needleswere removed cleanly with little to no plastic.

The needles from the coated syringes were cut into two sections, onenear the needle tip approximately 11 mm long and the other sectionclosest to the syringe body approximately 9 mm long. This was done todetermine, if Si was present, where it was in the needle. The needleswere placed in labeled 5 ml COP vials with 0.1 N KOH (2.0 ml coatedsyringe needles and 6.0 ml uncoated syringe needles). The vials wereplaced in a vacuum of approximately 28 inches Hg for one minute, toremove any air which was trapped in the needles. The vials were sealedwith a 20 mm washed plastic stopper and crimped with an aluminum crimpcap. The vials were autoclaved at 121° C. for 60 minutes. After thevials had cooled to room temperature the solutions were transferred into15 ml polypropylene tubes until testing was performed. Si in solutionwas performed by ICP/OES (inductively coupled plasma-optical emissionspectroscopy).

The second tested utilized 97 coated staked-needle 1 ml. capacity longstyle syringes, tri-layer PECVD coated (with a barrier coating or layer30, a pH protective coating or layer 34, and a lubricity layer asdiscussed in U.S. Pat. No. 7,985,188). These syringes were ethyleneoxide sterilized. 100 uncoated COP 1 ml long staked needle syringes wereused as a comparison. Testing was performed in the same manner as above.The results are shown in Tables 3 and 4.

The results from the first study are shown in Table 3. In that study thecoated syringes had received only barrier coating. The needles from theuncoated syringes (0.155 μg/syringe) had more Si present than theneedles from the coated syringes (0.102 μg/syringe) demonstrating thatthe coating process did not add any coating. The absence of Si fromcoated syringe needles is further demonstrated by the Si per unit lengthof needle (μg Si/mm). If a coating was present it would be expected thatthe portion of the needle closest to the syringe would have a higher Siper unit length than the portion of the needle furthest from thesyringe. This was not observed.

The results from the second study in Table 4 again show that thedifference in Si found in needles from coated syringes and needles fromuncoated syringes was not significant. The amount of Si per unit lengthof needle was essentially the same regardless of the location of theneedle.

The presence of some Si in needles was expected as stainless steelcontains approximately 1% Si by weight. The weight of the needles usedin these syringes was approximately 11 mg (11000 μg), therefore a Siresult of 0.1-0.2 μg/syringe is not unreasonable.

It was concluded from these studies that there is no coating, or at aminimum essentially no coating, in the internal diameters of the needlesof syringes coated by any of the coating processes used for the syringestested in this study.

TABLE 1 1st 2nd Delta Sample (mbar) (mbar) (mbar) 1 990.7 985.8 4.9 2990.7 985.6 5.1 3 990.7 985.7 5.0 4 991.0 986.4 4.6 5 991.5 986.8 4.7 6991.9 987.2 4.7 7 991.2 986.2 5.0 8 991.3 986.5 4.8 9 991.8 987.4 4.410  992.1 987.6 4.5 Avg 991.3 986.5 4.8 Max 992.1 987.6 5.1 Min 990.7985.6 4.4 StDev 0.5 0.7 0.2

TABLE 2 1st 2nd Delta Sample (mbar) (mbar) (mbar) #1Known Failure (2 μm)988.3 976.3 12.0 #2Known Failure (2 μm) 987.6 974.9 12.7 #3Known Failure(2 μm) 987.4 969.9 17.5 #4Known Failure (2 μm) 987.4 973.9 13.5 #5KnownFailure (2 μm) 987.7 976.1 11.6 Avg 987.7 974.2 13.5 Max 988.3 976.317.5 Min 987.4 969.9 11.6 StDev 0.4 2.6 2.4

TABLE 3 First Test (1-PECVD coating cycle) # of Result Syringe Samplesyringes (μg Si/syringe) (μg Si/mm needle) Uncoated syringe 100 0.1550.078 Total coated needles 96 0.102 0.050 Coated needle tip end 96 0.0640.058 Coated syringe end 96 0.038 0.051

TABLE 4 Second Test (3- PECVD coating cycles) # of Result Syringe Samplesyringes (μg Si/syringe) (μg Si/mm needle) Uncoated syringe 100 0.2200.011 Total coated needles 97 0.244 0.012 Coated needle tip end 97 0.1230.011 Coated syringe end 97 0.121 0.013

1. A method comprising: providing a capped pre-assembly comprising: abarrel comprising an internal wall defining a barrel lumen and a frontopening through the internal wall; and a cap secured to the barrel andat least substantially isolating the front opening from pressureconditions outside the cap; and applying a vapor-deposited coating orlayer directly or indirectly to at least a portion of the internal wallof the barrel, while the pre-assembly is capped, under conditionseffective to maintain communication between the barrel lumen and theexterior via the front opening at the end of the applying step.
 2. Theinvention of claim 1, in which the capped pre-assembly further comprisesa dispensing portion secured to the barrel, the dispensing portioncomprising a distal opening located outside the barrel, and a dispensingportion lumen communicating between the front opening and the distalopening of the dispensing portion.
 3. The invention of claim 1, furthercomprising, before the providing step, assembling the cappedpre-assembly.
 4. The invention of claim 3, further comprising, beforethe assembling step, forming the barrel.
 5. (canceled)
 6. (canceled) 7.The invention of claim 4, in which the barrel is formed by placing adispensing portion in an injection mold and injection molding thethermoplastic material about the dispensing portion, thus forming thebarrel and securing the dispensing portion to the barrel.
 8. (canceled)9. (canceled)
 10. (canceled)
 11. The invention of claim 2, in which thecap is made of a thermoplastic elastomer.
 12. The invention of claim 2,in which the cap of the pre-assembly isolates the distal opening atleast partially due to: contact between the cap and the distal opening,contact between the cap and the barrel, or both.
 13. The invention ofclaim 2, in which the cap is sufficiently permeable to a sterilizing gasto sterilize the portions of the assembly isolated by the cap. 14.(canceled)
 15. (canceled)
 16. (canceled)
 17. The invention of claim 2,in which there is substantially no deposition of the vapor-depositedcoating or layer in the dispensing portion lumen.
 18. The invention ofclaim 2, in which the barrel further comprises an opening spaced fromthe dispensing portion and communicating through the internal wall. 19.The invention of claim 18, in which the vapor-deposited coating or layeris applied through the opening.
 20. The invention of claim 19, in whichthe vapor-deposited coating or layer is applied by flowing a reactantvapor material through the opening and employing chemical vapordeposition to deposit a reaction product of the reactant vapor materialon the internal wall of the barrel.
 21. (canceled)
 22. (canceled) 23.(canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)28. (canceled)
 29. (canceled)
 30. (canceled)
 31. (canceled) 32.(canceled)
 33. (canceled)
 34. (canceled)
 35. (canceled)
 36. (canceled)37. (canceled)
 38. (canceled)
 39. (canceled)
 40. The invention of claim2 further comprising, while drawing at least a partial vacuum throughthe barrel opening, measuring the pressure decay of gas drawn from thebarrel opening and any leakage paths.
 41. The invention of claim 40,further comprising comparing the pressure decay of gas to apredetermined standard to determine the container closure integrity ofthe capped pre-assembly.
 42. The invention of claim 41, in which thepressure decay is measured with sufficient precision to detect apressure decay due to an intact container versus a container having asingle perforation in the cap having a diameter of 5 microns.
 43. Theinvention of claim 42, in which the pressure decay is measured within atime between 1 second and 60 seconds.
 44. (canceled)
 45. (canceled) 46.The invention of claim 40, in which the pressure decay of gas drawn fromthe barrel opening and any leakage paths is measured after applying avapor-deposited coating or layer.
 47. The invention of claim 2, in whichthe vapor-deposited coating or layer is a barrier coating or layer. 48.(canceled)
 49. (canceled)
 50. (canceled)
 51. (canceled)
 52. (canceled)53. (canceled)
 54. (canceled)
 55. (canceled)
 56. (canceled) 57.(canceled)
 58. (canceled)
 59. (canceled)
 60. (canceled)
 61. (canceled)62. (canceled)
 63. The invention of claim 2, in which the dispensingportion is a hypodermic needle or a needle-free dispenser.
 64. Aprefilled medical syringe or cartridge comprising a capped pre-assemblycomprising: a barrel comprising an internal wall defining a barrel lumenand a front opening through the internal wall; a cap secured to thebarrel and at least substantially isolating the front opening frompressure conditions outside the cap; and a dispensing portion secured tothe barrel, the dispensing portion comprising a distal opening locatedoutside the barrel, and a dispensing portion lumen communicating betweenthe front opening of the barrel and the distal opening of the dispensingportion; a piston or plunger tip closing the pre-assembly, and amaterial in the barrel lumen selected from the group consisting of anyone or more of the following: Injectable Drugs Ablavar (GadofosvesetTrisodium Injection) Abarelix Depot Abobotulinumtoxin A Injection(Dysport) ABT-263 ABT-869 ABX-EFG Accretropin (Somatropin Injection)Acetadote (Acetylcysteine Injection) Acetazolamide Injection(Acetazolamide Injection) Acetylcysteine Injection (Acetadote) Actemra(Tocilizumab Injection) Acthrel (Corticorelin Ovine Triflutate forInjection) Actummune Activase Acyclovir for Injection (ZoviraxInjection) Adacel Adalimumab Adenoscan (Adenosine Injection) AdenosineInjection (Adenoscan) Adrenaclick AdreView (Iobenguane I 123 Injectionfor Intravenous Use) Afluria Ak-Fluor (Fluorescein Injection) Aldurazyme(Laronidase) Alglucerase Injection (Ceredase) Alkeran Injection(Melphalan Hcl Injection) Allopurinol Sodium for Injection (Aloprim)Aloprim (Allopurinol Sodium for Injection) Alprostadil Alsuma(Sumatriptan Injection) ALTU-238 Amino Acid Injections Aminosyn ApidraApremilast Alprostadil Dual Chamber System for Injection (CaverjectImpulse) AMG 009 AMG 076 AMG 102 AMG 108 AMG 114 AMG 162 AMG 220 AMG 221AMG 222 AMG 223 AMG 317 AMG 379 AMG 386 AMG 403 AMG 477 AMG 479 AMG 517AMG 531 AMG 557 AMG 623 AMG 655 AMG 706 AMG 714 AMG 745 AMG 785 AMG 811AMG 827 AMG 837 AMG 853 AMG 951 Amiodarone HCl Injection (Amiodarone HClInjection) Amobarbital Sodium Injection (Amytal Sodium) Amytal Sodium(Amobarbital Sodium Injection) Anakinra Anti-Abeta Anti-Beta7Anti-Beta20 Anti-CD4 Anti-CD20 Anti-CD40 Anti-IFNalpha Anti-IL13Anti-OX40L Anti-oxLDS Anti-NGF Anti-NRP1 Arixtra Amphadase(Hyaluronidase Inj) Ammonul (Sodium Phenylacetate and Sodium BenzoateInjection) Anaprox Anzemet Injection (Dolasetron Mesylate Injection)Apidra (Insulin Glulisine [rDNA origin] Inj) Apomab Aranesp (darbepoetinalfa) Argatroban (Argatroban Injection) Arginine Hydrochloride Injection(R-Gene 10 Aristocort Aristospan Arsenic Trioxide Injection (Trisenox)Articane HCl and Epinephrine Injection (Septocaine) Arzerra (OfatumumabInjection) Asclera (Polidocanol Injection) Ataluren Ataluren-DMDAtenolol Inj (Tenormin I.V. Injection) Atracurium Besylate Injection(Atracurium Besylate Injection) Avastin Azactam Injection (AztreonamInjection) Azithromycin (Zithromax Injection) Aztreonam Injection(Azactam Injection) Baclofen Injection (Lioresal Intrathecal)Bacteriostatic Water (Bacteriostatic Water for Injection) BaclofenInjection (Lioresal Intrathecal) Bal in Oil Ampules (DimercarprolInjection) BayHepB BayTet Benadryl Bendamustine Hydrochloride Injection(Treanda) Benztropine Mesylate Injection (Cogentin) BetamethasoneInjectable Suspension (Celestone Soluspan) Bexxar Bicillin C—R 900/300(Penicillin G Benzathine and Penicillin G Procaine Injection) Blenoxane(Bleomycin Sulfate Injection) Bleomycin Sulfate Injection (Blenoxane)Boniva Injection (Ibandronate Sodium Injection) Botox Cosmetic(OnabotulinumtoxinA for Injection) BR3-FC Bravelle (UrofollitropinInjection) Bretylium (Bretylium Tosylate Injection) Brevital Sodium(Methohexital Sodium for Injection) Brethine Briobacept BTT-1023Bupivacaine HCl Byetta Ca-DTPA (Pentetate Calcium Trisodium Inj)Cabazitaxel Injection (Jevtana) Caffeine Alkaloid (Caffeine and SodiumBenzoate Injection) Calcijex Injection (Calcitrol) Calcitrol (CalcijexInjection) Calcium Chloride (Calcium Chloride Injection 10%) CalciumDisodium Versenate (Edetate Calcium Disodium Injection) Campath(Altemtuzumab) Camptosar Injection (Irinotecan Hydrochloride)Canakinumab Injection (IIaris) Capastat Sulfate (Capreomycin forInjection) Capreomycin for Injection (Capastat Sulfate) Cardiolite (Prepkit for Technetium Tc99 Sestamibi for Injection) Carticel CathfloCefazolin and Dextrose for Injection (Cefazolin Injection) CefepimeHydrochloride Cefotaxime Ceftriaxone Cerezyme Carnitor InjectionCaverject Celestone Soluspan Celsior Cerebyx (Fosphenyloin SodiumInjection) Ceredase (Alglucerase Injection) Ceretec (Technetium Tc99mExametazime Injection) Certolizumab CF-101 Chloramphenicol SodiumSuccinate (Chloramphenicol Sodium Succinate Injection) ChloramphenicolSodium Succinate Injection (Chloramphenicol Sodium Succinate)Cholestagel (Colesevelam HCL) Choriogonadotropin Alfa Injection(Ovidrel) Cimzia Cisplatin (Cisplatin Injection) Clolar (ClofarabineInjection) Clomiphine Citrate Clonidine Injection (Duraclon) Cogentin(Benztropine Mesylate Injection) Colistimethate Injection (Coly-Mycin M)Coly-Mycin M (Colistimethate Injection) Cornpath Conivaptan HclInjection (Vaprisol) Conjugated Estrogens for Injection (PremarinInjection) Copaxone Corticorelin Ovine Triflutate for Injection(Acthrel) Corvert (Ibutilide Fumarate Injection) Cubicin (DaptomycinInjection) CF-101 Cyanokit (Hydroxocobalamin for Injection) CytarabineLiposome Injection (DepoCyt) Cyanocobalamin Cytovene (ganciclovir)D.H.E. 45 Dacetuzumab Dacogen (Decitabine Injection) Dalteparin DantriumIV (Dantrolene Sodium for Injection) Dantrolene Sodium for Injection(Dantrium IV) Daptomycin Injection (Cubicin) Darbepoietin Alfa DDAVPInjection (Desmopressin Acetate Injection) Decavax Decitabine Injection(Dacogen) Dehydrated Alcohol (Dehydrated Alcohol Injection) DenosumabInjection (Prolia) Delatestryl Delestrogen Delteparin Sodium Depacon(Valproate Sodium Injection) Depo Medrol (Methylprednisolone AcetateInjectable Suspension) DepoCyt (Cytarabine Liposome Injection) DepoDur(Morphine Sulfate XR Liposome Injection) Desmopressin Acetate Injection(DDAVP Injection) Depo-Estradiol Depo-Provera 104 mg/ml Depo-Provera 150mg/ml Depo-Testosterone Dexrazoxane for Injection, Intravenous InfusionOnly (Totect) Dextrose/Electrolytes Dextrose and Sodium Chloride lnj(Dextrose 5% in 0.9% Sodium Chloride) Dextrose Diazepam Injection(Diazepam Injection) Digoxin Injection (Lanoxin Injection) Dilaudid-HP(Hydromorphone Hydrochloride Injection) Dimercarprol Injection (Bal inOil Ampules) Diphenhydramine Injection (Benadryl Injection) DipyridamoleInjection (Dipyridamole Injection) DMOAD Docetaxel for Injection(Taxotere) Dolasetron Mesylate Injection (Anzemet Injection) Doribax(Doripenem for Injection) Doripenem for Injection (Doribax)Doxercalciferol Injection (Hectorol Injection) Doxil (Doxorubicin HclLiposome Injection) Doxorubicin Hcl Liposome Injection (Doxil) Duraclon(Clonidine Injection) Duramorph (Morphine Injection) Dysport(Abobotulinumtoxin A Injection) Ecallantide Injection (Kalbitor)EC-Naprosyn (naproxen) Edetate Calcium Disodium Injection (CalciumDisodium Versenate) Edex (Alprostadil for Injection) Engerix EdrophoniumInjection (Enlon) Eliglustat Tartate Eloxatin (Oxaliplatin Injection)Emend Injection (Fosaprepitant Dimeglumine Injection) EnalaprilatInjection (Enalaprilat Injection) EnIon (Edrophonium Injection)Enoxaparin Sodium Injection (Lovenox) Eovist (Gadoxetate DisodiumInjection) Enbrel (etanercept) Enoxaparin Epicel Epinepherine EpipenEpipen Jr. Epratuzumab Erbitux Ertapenem Injection (Invanz)Erythropoieten Essential Amino Acid Injection (Nephramine) EstradiolCypionate Estradiol Valerate Etanercept Exenatide Injection (Byetta)Evlotra Fabrazyme (Adalsidase beta) Famotidine Injection FDG(Fludeoxyglucose F 18 Injection) Feraheme (Ferumoxytol Injection)Feridex I.V. (Ferumoxides Injectable Solution) Fertinex FerumoxidesInjectable Solution (Feridex I.V.) Ferumoxytol Injection (Feraheme)Flagyl Injection (Metronidazole Injection) Fluarix Fludara (FludarabinePhosphate) Fludeoxyglucose F 18 Injection (FDG) Fluorescein Injection(Ak-Fluor) Follistim AQ Cartridge (Follitropin Beta Injection)Follitropin Alfa Injection (Gonal-f RFF) Follitropin Beta Injection(Follistim AQ Cartridge) Folotyn (Pralatrexate Solution for IntravenousInjection) Fondaparinux Forteo (Teriparatide (rDNA origin) Injection)Fostamatinib Fosaprepitant Dimeglumine Injection (Emend Injection)Foscarnet Sodium Injection (Foscavir) Foscavir (Foscarnet SodiumInjection) Fosphenyloin Sodium Injection (Cerebyx) Fospropofol DisodiumInjection (Lusedra) Fragmin Fuzeon (enfuvirtide) GA101 GadobenateDimeglumine Injection (Multihance) Gadofosveset Trisodium Injection(Ablavar) Gadoteridol Injection Solution (ProHance) GadoversetamideInjection (OptiMARK) Gadoxetate Disodium Injection (Eovist) Ganirelix(Ganirelix Acetate Injection) Gardasil GC1008 GDFD Gemtuzumab Ozogamicinfor Injection (Mylotarg) Genotropin Gentamicin Injection GENZ-112638Golimumab Injection (Simponi Injection) Gonal-f RFF (Follitropin AlfaInjection) Granisetron Hydrochloride (Kytril Injection) GentamicinSulfate Glatiramer Acetate Glucagen Glucagon HAE1 Haldol (HaloperidolInjection) Havrix Hectorol Injection (Doxercalciferol Injection)Hedgehog Pathway Inhibitor Heparin Herceptin hG-CSF Humalog Human GrowthHormone Humatrope HuMax Humegon Hurnira Humulin Ibandronate SodiumInjection (Boniva Injection) Ibuprofen Lysine Injection (NeoProfen)Ibutilide Fumarate Injection (Corvert) Idamycin PFS (IdarubicinHydrochloride Injection) Idarubicin Hydrochloride Injection (IdamycinPFS) Ilaris (Canakinumab Injection) Imipenem and Cilastatin forInjection (Primaxin I.V.) Imitrex Incobotulinumtoxin A for Injection(Xeomin) Increlex (Mecasermin [rDNA origin] Injection) Indocin IV(Indomethacin Inj) Indomethacin Inj (Indocin IV) Infanrix InnohepInsulin Insulin Aspart [rDNA origin] lnj (NovoLog) Insulin Glargine[rDNA origin] Injection (Lantus) Insulin Glulisine [rDNA origin] Inj(Apidra) Interferon alfa-2b, Recombinant for Injection (Intron A) IntronA (Interferon alfa-2b, Recombinant for Injection) Invanz (ErtapenemInjection) Invega Sustenna (Paliperidone Palmitate Extended-ReleaseInjectable Suspension) Invirase (saquinavir mesylate) Iobenguane I 123Injection for Intravenous Use (AdreView) Iopromide Injection (Ultravist)Ioversol Injection (Optiray Injection) Iplex (Mecasermin Rinfabate [rDNAorigin] Injection) Iprivask Irinotecan Hydrochloride (CamptosarInjection) Iron Sucrose Injection (Venofer) Istodax (Romidepsin forInjection) Itraconazole Injection (Sporanox Injection) Jevtana(Cabazitaxel Injection) Jonexa Kalbitor (Ecallantide Injection) KCL inD5NS (Potassium Chloride in 5% Dextrose and Sodium Chloride Injection)KCL in D5W KCL in NS Kenalog 10 Injection (Triamcinolone AcetonideInjectable Suspension) Kepivance (Palifermin) Keppra Injection(Levetiracetam) Keratinocyte KFG Kinase Inhibitor Kineret (Anakinra)Kinlytic (Urokinase Injection) Kin rix Klonopin (clonazepam) KytrilInjection (Granisetron Hydrochloride) lacosamide Tablet and Injection(Vimpat) Lactated Ringer's Lanoxin Injection (Digoxin Injection)Lansoprazole for Injection (Prevacid I.V.) Lantus Leucovorin Calcium(Leucovorin Calcium Injection) Lente (L) Leptin Levemir LeukineSargramostim Leuprolide Acetate Levothyroxine Levetiracetam (KeppraInjection) Lovenox Levocarnitine Injection (Carnitor Injection) Lexiscan(Regadenoson Injection) Lioresal Intrathecal (Baclofen Injection)Liraglutide [rDNA] Injection (Victoza) Lovenox (Enoxaparin SodiumInjection) Lucentis (Ranibizumab Injection) Lumizyme Lupron (LeuprolideAcetate Injection) Lusedra (Fospropofol Disodium Injection) MaciMagnesium Sulfate (Magnesium Sulfate Injection) Mannitol Injection(Mannitol IV) Marcaine (Bupivacaine Hydrochloride and EpinephrineInjection) Maxipime (Cefepime Hydrochloride for Injection) MDP MultidoseKit of Technetium Injection (Technetium Tc99m Medronate Injection)Mecasermin [rDNA origin] Injection (Increlex) Mecasermin Rinfabate [rDNAorigin] Injection (lplex) Melphalan Hcl Injection (Alkeran Injection)Methotrexate Menactra Menopur (Menotropins Injection) Menotropins forInjection (Repronex) Methohexital Sodium for Injection (Brevital Sodium)Methyldopate Hydrochloride Injection, Solution (Methyldopate Hcl)Methylene Blue (Methylene Blue Injection) Methylprednisolone AcetateInjectable Suspension (Depo Medrol) MetMab Metoclopramide Injection(Reglan Injection) Metrodin (Urofollitropin for Injection) MetronidazoleInjection (Flagyl Injection) Miacalcin Midazolam (Midazolam Injection)Mimpara (Cinacalet) Minocin Injection (Minocycline Inj) Minocycline Inj(Minocin Injection) Mipomersen Mitoxantrone for Injection Concentrate(Novantrone) Morphine Injection (Duramorph) Morphine Sulfate XR LiposomeInjection (DepoDur) Morrhuate Sodium (Morrhuate Sodium Injection)Motesanib Mozobil (Plerixafor Injection) Multihance (GadobenateDimeglumine Injection) Multiple Electrolytes and Dextrose InjectionMultiple Electrolytes Injection Mylotarg (Gemtuzumab Ozogamicin forInjection) Myozyme (Alglucosidase alfa) Nafcillin Injection (NafcillinSodium) Nafcillin Sodium (Nafcillin Injection) Naltrexone XR Inj(Vivitrol) Naprosyn (naproxen) NeoProfen (Ibuprofen Lysine Injection)Nandrol Decanoate Neostigmine Methylsulfate (Neostigmine MethylsulfateInjection) NEO-GAA NeoTect (Technetium Tc 99m Depreotide Injection)Nephramine (Essential Amino Acid Injection) Neulasta (pegfilgrastim)Neupogen (Filgrastim) Novolin Novolog NeoRecormon Neutrexin(Trimetrexate Glucuronate Inj) NPH(N) Nexterone (Amiodarone HClInjection) Norditropin (Somatropin Injection) Normal Saline (SodiumChloride Injection) Novantrone (Mitoxantrone for Injection Concentrate)Novolin 70/30 Innolet (70% NPH, Human Insulin Isophane Suspension and30% Regular, Human Insulin Injection) NovoLog (Insulin Aspart [rDNAorigin] Inj) Nplate (romiplostim) Nutropin (Somatropin (rDNA origin) forInj) Nutropin AQ Nutropin Depot (Somatropin (rDNA origin) for Inj)Octreotide Acetate Injection (Sandostatin LAR) Ocrelizumab OfatumumabInjection (Arzerra) Olanzapine Extended Release Injectable Suspension(Zyprexa Relprevv) Omnitarg Omnitrope (Somatropin [rDNA origin]Injection) Ondansetron Hydrochloride Injection (Zofran Injection)OptiMARK (Gadoversetamide Injection) Optiray Injection (loversolInjection) Orencia Osmitrol Injection in Aviva (Mannitol Injection inAviva Plastic Vessel 250) Osmitrol Injection in Viaflex (MannitolInjection in Viaflex Plastic Vessel 250) Osteoprotegrin Ovidrel(Choriogonadotropin Alfa Injection) Oxacillin (Oxacillin for Injection)Oxaliplatin Injection (Eloxatin) Oxytocin Injection (Pitocin)Paliperidone Palmitate Extended-Release Injectable Suspension (InvegaSustenna) Pamidronate Disodium Injection (Pamidronate DisodiumInjection) Panitumumab Injection for Intravenous Use (Vectibix)Papaverine Hydrochloride Injection (Papaverine Injection) PapaverineInjection (Papaverine Hydrochloride Injection) Parathyroid HormoneParicalcitol Injection Fliptop Vial (Zemplar Injection) PARP InhibitorPediarix PEGIntron Peginterferon Pegfilgrastim Penicillin G Benzathineand Penicillin G Procaine Pentetate Calcium Trisodium Inj (Ca-DTPA)Pentetate Zinc Trisodium Injection (Zn-DTPA) Pepcid Injection(Famotidine Injection) Pergonal Pertuzumab Phentolamine Mesylate(Phentolamine Mesylate for Injection) Physostigmine Salicylate(Physostigmine Salicylate (injection)) Physostigmine Salicylate(injection) (Physostigmine Salicylate) Piperacillin and TazobactamInjection (Zosyn) Pitocin (Oxytocin Injection) Plasma-Lyte 148 (MultipleElectrolytes Inj) Plasma-Lyte 56 and Dextrose (Multiple Electrolytes andDextrose Injection in Viaflex Plastic Vessel 250) PlasmaLyte PlerixaforInjection (Mozobil) Polidocanol Injection (Asclera) Potassium ChloridePralatrexate Solution for Intravenous Injection (Folotyn) PramlintideAcetate Injection (Symlin) Premarin Injection (Conjugated Estrogens forInjection) Prep kit for Technetium Tc99 Sestamibi for Injection(Cardiolite) Prevacid I.V. (Lansoprazole for Injection) Primaxin I.V.(Imipenem and Cilastatin for Injection) Prochymal Procrit ProgesteroneProHance (Gadoteridol Injection Solution) Prolia (Denosumab Injection)Promethazine HCl Injection (Promethazine Hydrochloride Injection)Propranolol Hydrochloride Injection (Propranolol HydrochlorideInjection) Quinidine Gluconate Injection (Quinidine Injection) QuinidineInjection (Quinidine Gluconate Injection) R-Gene 10 (ArginineHydrochloride Injection) Ranibizumab Injection (Lucentis) RanitidineHydrochloride Injection (Zantac Injection) Raptiva Reclast (ZoledronicAcid Injection) Recombivarix HB Regadenoson Injection (Lexiscan) ReglanInjection (Metoclopramide Injection) Remicade Renagel Renvela (SevelamerCarbonate) Repronex (Menotropins for Injection) Retrovir IV (ZidovudineInjection) rhApo2L/TRAIL Ringer's and 5% Dextrose Injection (Ringers inDextrose) Ringer's Injection (Ringers Injection) Rituxan RituximabRocephin (ceftriaxone) Rocuronium Bromide Injection (Zemuron) Roferon-A(interferon alfa-3) Romazicon (flumazenil) Romidepsin for Injection(Istodax) Saizen (Somatropin Injection) Sandostatin LAR (OctreotideAcetate Injection) Sclerostin Ab Sensipar (cinacalcet) Sensorcaine(Bupivacaine HCl Injections) Septocaine (Articane HCl and EpinephrineInjection) Serostim LQ (Somatropin (rDNA origin) Injection) SimponiInjection (Golimumab Injection) Sodium Acetate (Sodium AcetateInjection) Sodium Bicarbonate (Sodium Bicarbonate 5% Injection) SodiumLactate (Sodium Lactate Injection in AVIVA) Sodium Phenylacetate andSodium Benzoate Injection (Ammonul) Somatropin (rDNA origin) for Inj(Nutropin) Sporanox Injection (Itraconazole Injection) Stelara Injection(Ustekinumab) Stemgen Sufenta (Sufentanil Citrate Injection) SufentanilCitrate Injection (Sufenta) Sumavel Sumatriptan Injection (Alsuma)Symlin Symlin Pen Systemic Hedgehog Antagonist Synvisc-One (Hylan G-F 20Single Intra-articular Injection) Tarceva Taxotere (Docetaxel forInjection) Technetium Tc 99m Telavancin for Injection (Vibativ)Temsirolimus Injection (Torisel) Tenormin I.V. Injection (Atenolol Inj)Teriparatide (rDNA origin) Injection (Forteo) Testosterone CypionateTestosterone Enanthate Testosterone Propionate Tev-Tropin (Somatropin,rDNA Origin, for Injection) tgAAC94 Thallous Chloride TheophyllineThiotepa (Thiotepa Injection) Thymoglobulin (Anti-Thymocyte Globulin(Rabbit) Thyrogen (Thyrotropin Alfa for Injection) Ticarcillin Disodiumand Clavulanate Potassium Galaxy (Timentin Injection) Tigan Injection(Trimethobenzamide Hydrochloride Injectable) Timentin Injection(Ticarcillin Disodium and Clavulanate Potassium Galaxy) TNKaseTobramycin Injection (Tobramycin Injection) Tocilizumab Injection(Actemra) Torisel (Temsirolimus Injection) Totect (Dexrazoxane forInjection, Intravenous Infusion Only) Trastuzumab-DM1 Travasol (AminoAcids (Injection)) Treanda (Bendamustine Hydrochloride Injection)Trelstar (Triptorelin Pamoate for Injectable Suspension) TriamcinoloneAcetonide Triamcinolone Diacetate Triamcinolone Hexacetonide InjectableSuspension (Aristospan Injection 20 mg) Triesence (TriamcinoloneAcetonide Injectable Suspension) Trimethobenzamide HydrochlorideInjectable (Tigan Injection) Trimetrexate Glucuronate Inj (Neutrexin)Triptorelin Pamoate for Injectable Suspension (Trelstar) TwinjectTrivaris (Triamcinolone Acetonide Injectable Suspension) Trisenox(Arsenic Trioxide Injection) Twinrix Typhoid Vi Ultravist (lopromideInjection) Urofollitropin for Injection (Metrodin) Urokinase Injection(Kinlytic) Ustekinumab (Stelara Injection) Ultralente (U) Valium(diazepam) Valproate Sodium Injection (Depacon) Valtropin (SomatropinInjection) Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection)Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride) Vaprisol(Conivaptan Hcl Injection) VAQTA Vasovist (Gadofosveset TrisodiumInjection for Intravenous Use) Vectibix (Panitumumab Injection forIntravenous Use) Venofer (Iron Sucrose Injection) Verteporfin Inj(Visudyne) Vibativ (Telavancin for Injection) Victoza (Liraglutide[rDNA] Injection) Vimpat (lacosamide Tablet and Injection) VinblastineSulfate (Vinblastine Sulfate Injection) Vincasar PFS (VincristineSulfate Injection) Victoza Vincristine Sulfate (Vincristine SulfateInjection) Visudyne (Verteporfin Inj) Vitamin B-12 Vivitrol (NaltrexoneXR Inj) Voluven (Hydroxyethyl Starch in Sodium Chloride Injection)Xeloda Xenical (orlistat) Xeomin (Incobotulinumtoxin A for Injection)Xolair Zantac Injection (Ranitidine Hydrochloride Injection) ZemplarInjection (Paricalcitol Injection Fliptop Vial) Zemuron (RocuroniumBromide Injection) Zenapax (daclizumab) Zevalin Zidovudine Injection(Retrovir IV) Zithromax Injection (Azithromycin) Zn-DTPA (Pentetate ZincTrisodium Injection) Zofran Injection (Ondansetron HydrochlorideInjection) Zingo Zoledronic Acid for Inj (Zometa) Zoledronic AcidInjection (Reclast) Zometa (Zoledronic Acid for Inj) Zosyn (Piperacillinand Tazobactam Injection) Zyprexa Relprevv (Olanzapine Extended ReleaseInjectable Suspension) Liquid Drugs (Non-Injectable) Abilify AccuNeb(Albuterol Sulfate Inhalation Solution) Actidose Aqua (ActivatedCharcoal Suspension) Activated Charcoal Suspension (Actidose Aqua)Advair Agenerase Oral Solution (Amprenavir Oral Solution) Akten(Lidocaine Hydrochloride Ophthalmic Gel) Alamast (Pemirolast PotassiumOphthalmic Solution) Albumin (Human) 5% Solution (Buminate 5%) AlbuterolSulfate Inhalation Solution Alinia Alocril Alphagan Alrex AlvescoAmprenavir Oral Solution Analpram-HC Arformoterol Tartrate InhalationSolution (Brovana) Aristospan Injection 20 mg (TriamcinoloneHexacetonide Injectable Suspension) Asacol Asmanex Astepro Astepro(Azelastine Hydrochloride Nasal Spray) Atrovent Nasal Spray (IpratropiumBromide Nasal Spray) Atrovent Nasal Spray 0.06 Augmentin ES-600 Azasite(Azithromycin Ophthalmic Solution) Azelaic Acid (Finacea Gel) AzelastineHydrochloride Nasal Spray (Astepro) Azelex (Azelaic Acid Cream) Azopt(Brinzolamide Ophthalmic Suspension) Bacteriostatic Saline Balanced SaltBepotastine Bactroban Nasal Bactroban Beclovent Benzac W BetimolBetoptic S Bepreve Bimatoprost Ophthalmic Solution Bleph 10(Sulfacetamide Sodium Ophthalmic Solution 10%) Brinzolamide OphthalmicSuspension (Azopt) Bromfenac Ophthalmic Solution (Xibrom) BromhistBrovana (Arformoterol Tartrate Inhalation Solution) BudesonideInhalation Suspension (Pulmicort Respules) Cambia (Diclofenac Potassiumfor Oral Solution) Capex Carac Carboxine-PSE Carnitor Cayston (Aztreonamfor Inhalation Solution) Cellcept Centany Cerumenex Ciloxan OphthalmicSolution (Ciprofloxacin HCL Ophthalmic Solution) Ciprodex CiprofloxacinHCL Ophthalmic Solution (Ciloxan Ophthalmic Solution) ClemastineFumarate Syrup (Clemastine Fumarate Syrup) CoLyte (PEG ElectrolytesSolution) Combiven Comtan Condylox Cordran Cortisporin OphthalmicSuspension Cortisporin Otic Suspension Cromolyn Sodium InhalationSolution (Intal Nebulizer Solution) Cromolyn Sodium Ophthalmic Solution(Opticrom) Crystalline Amino Acid Solution with Electrolytes (AminosynElectrolytes) Cutivate Cuvposa (Glycopyrrolate Oral Solution)Cyanocobalamin (CaloMist Nasal Spray) Cyclosporine Oral Solution(Gengraf Oral Solution) Cyclogyl Cysview (Hexamino)evulinateHydrochloride Intravesical Solution) DermOtic Oil (FluocinoloneAcetonide Oil Ear Drops) Desmopressin Acetate Nasal Spray DDAVPDerma-Smoothe/FS Dexamethasone Intensol Dianeal Low Calcium Dianeal PDDiclofenac Potassium for Oral Solution (Cambia) Didanosine PediatricPowder for Oral Solution (Videx) Differin Dilantin 125 (Phenyloin OralSuspension) Ditropan Dorzolamide Hydrochloride Ophthalmic Solution(Trusopt) Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution(Cosopt) Dovonex Scalp (Calcipotriene Solution) Doxycycline Calcium OralSuspension (Vibramycin Oral) Efudex Elaprase (Idursulfase Solution)Elestat (Epinastine HCl Ophthalmic Solution) Elocon Epinastine HClOphthalmic Solution (Elestat) Epivir HBV Epogen (Epoetin alfa)Erythromycin Topical Solution 1.5% (Staticin) Ethiodol (Ethiodized Oil)Ethosuximide Oral Solution (Zarontin Oral Solution) Eurax Extraneal(Icodextrin Peritoneal Dialysis Solution) Felbatol Feridex I.V.(Ferumoxides Injectable Solution) Flovent Floxin Otic (Ofloxacin OticSolution) Flo-Pred (Prednisolone Acetate Oral Suspension) FluoroplexFlunisolide Nasal Solution (Flunisolide Nasal Spray 0.025%)Fluorometholone Ophthalmic Suspension (FML) Flurbiprofen SodiumOphthalmic Solution (Ocufen) FML Foradil Formoterol Fumarate InhalationSolution (Perforomist) Fosamax Furadantin (Nitrofurantoin OralSuspension) Furoxone Gammagard Liquid (Immune Globulin Intravenous(Human) 10%) Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension)Gatifloxacin Ophthalmic Solution (Zymar) Gengraf Oral Solution(Cyclosporine Oral Solution) Glycopyrrolate Oral Solution (Cuvposa)Halcinonide Topical Solution (Halog Solution) Halog Solution(Halcinonide Topical Solution) HEP-LOCK U/P (Preservative-Free HeparinLock Flush Solution) Heparin Lock Flush Solution (Hepflush 10Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview)Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab Elixir)Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution) IAPAntagonist Isopto Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray)Itraconazole Oral Solution (Sporanox Oral Solution) KetorolacTromethamine Ophthalmic Solution (Acular LS) Kaletra Lanoxin LexivaLeuprolide Acetate for Depot Suspension (Lupron Depot 11.25 mg)Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon)Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor) LevofloxacinOphthalmic Solution 0.5% (Quixin) Lidocaine HCl Sterile Solution(Xylocalne MPF Sterile Solution) Lok Pak (Heparin Lock Flush Solution)Lorazepam Intensol Lortab Elixir (Hydrocodone Bitartrate andAcetaminophen Oral Solution) Lotemax (Loteprednol Etabonate OphthalmicSuspension) Loteprednol Etabonate Ophthalmic Suspension (Alrex) LowCalcium Peritoneal Dialysis Solutions (Dianeal Low Calcium) Lumigan(Bimatoprost Ophthalmic Solution 0.03% for Glaucoma) Lupron Depot 11.25mg (Leuprolide Acetate for Depot Suspension) Megestrol Acetate OralSuspension (Megestrol Acetate Oral Suspension) MEK Inhibitor MepronMesnex Mestinon Mesalamine Rectal Suspension Enema (Rowasa) Melquin-3Topical Solution (Hydroquinone 3% Topical Solution) MetMab MethyldopateHcl (Methyldopate Hydrochloride Injection, Solution) Methylin OralSolution (Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL)Methylprednisolone Acetate Injectable Suspension (Depo Medrol)Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL (MethylinOral Solution) Methylprednisolone sodium succinate (Solu Medrol)Metipranolol Ophthalmic Solution (Optipranolol) Migranal Miochol-E(Acetylcholine Chloride Intraocular Solution) Micro-K for LiquidSuspension (Potassium Chloride Extended Release Formulation for LiquidSuspension) Minocin (Minocycline Hydrochloride Oral Suspension) NasacortNeomycin and Polymyxin B Sulfates and Hydrocortisone NepafenacOphthalmic Suspension (Nevanac) Nevanac (Nepafenac OphthalmicSuspension) Nitrofurantoin Oral Suspension (Furadantin) Noxafil(Posaconazole Oral Suspension) Nystatin (oral) (Nystatin OralSuspension) Nystatin Oral Suspension (Nystatin (oral)) Ocufen(Flurbiprofen Sodium Ophthalmic Solution) Ofloxacin Ophthalmic Solution(Ofloxacin Ophthalmic Solution) Ofloxacin Otic Solution (Floxin Otic)Olopatadine Hydrochloride Ophthalmic Solution (Pataday) Opticrom(Cromolyn Sodium Ophthalmic Solution) Optipranolol (MetipranololOphthalmic Solution) Patanol Pediapred PerioGard Phenyloin OralSuspension (Dilantin 125) Phisohex Posaconazole Oral Suspension(Noxafil) Potassium Chloride Extended Release Formulation for LiquidSuspension (Micro-K for Liquid Suspension) Pataday (OlopatadineHydrochloride Ophthalmic Solution) Patanase Nasal Spray (OlopatadineHydrochloride Nasal Spray) PEG Electrolytes Solution (CoLyte) PemirolastPotassium Ophthalmic Solution (Alamast) Penlac (C₁₋clopirox TopicalSolution) PENNSAID (Diclofenac Sodium Topical Solution) Perforomist(Formoterol Fumarate Inhalation Solution) Peritoneal Dialysis SolutionPhenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine)Phospholine Iodide (Echothiophate Iodide for Ophthalmic Solution)Podofilox (Podofilox Topical Solution) Pred Forte (Prednisolone AcetateOphthalmic Suspension) Pralatrexate Solution for Intravenous Injection(Folotyn) Pred Mild Prednisone Intensol Prednisolone Acetate OphthalmicSuspension (Pred Forte) Prevacid PrismaSol Solution (SterileHemofiltration Hemodiafiltration Solution) ProAir Proglycem ProHance(Gadoteridol Injection Solution) Proparacaine Hydrochloride OphthalmicSolution (Alcaine) Propine Pulmicort Pulmozyme Quixin (LevofloxacinOphthalmic Solution 0.5%) QVAR Rapamune Rebetol Relacon-HC Rotarix(Rotavirus Vaccine, Live, Oral Suspension) Rotavirus Vaccine, Live, OralSuspension (Rotarix) Rowasa (Mesalamine Rectal Suspension Enema) Sabril(Vigabatrin Oral Solution) Sacrosidase Oral Solution (Sucraid)Sandimmune Sepra Serevent Diskus Solu Cortef (Hydrocortisone SodiumSuccinate) Solu Medrol (Methylprednisolone sodium succinate) SpirivaSporanox Oral Solution (Itraconazole Oral Solution) Staticin(Erythromycin Topical Solution 1.5%) Stalevo Starlix SterileHemofiltration Hemodiafiltration Solution (PrismaSol Solution) StimateSucralfate (Carafate Suspension) Sulfacetamide Sodium OphthalmicSolution 10% (Bleph 10 Synarel Nasal Solution (Nafarelin Acetate NasalSolution for Endometriosis) Taclonex Scalp (Calcipotriene andBetamethasone Dipropionate Topical Suspension) Tamiflu Tobi TobraDexTobradex ST (Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05%)Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex ST)Timolol Timoptic Travatan Z Treprostinil Inhalation Solution (Tyvaso)Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution) Tyvaso(Treprostinil Inhalation Solution) Ventolin Vfend Vibramycin Oral(Doxycycline Calcium Oral Suspension) Videx (Didanosine Pediatric Powderfor Oral Solution) Vigabatrin Oral Solution (Sabril) Viokase ViraceptViramune Vitamin K1 (Fluid Colloidal Solution of Vitamin K1) VoltarenOphthalmic (Diclofenac Sodium Ophthalmic Solution) Zarontin OralSolution (Ethosuximide Oral Solution) Ziagen Zyvox Zymar (GatifloxacinOphthalmic Solution) Zymaxid (Gatifloxacin Ophthalmic Solution) DrugClasses 5-alpha-reductase inhibitors 5-aminosalicylates 5HT3 receptorantagonists adamantane antivirals adrenal cortical steroids adrenalcorticosteroid inhibitors adrenergic bronchodilators agents forhypertensive emergencies agents for pulmonary hypertension aldosteronereceptor antagonists alkylating agents alpha-adrenoreceptor antagonistsalpha-glucosidase inhibitors alternative medicines amebicidesaminoglycosides aminopenicillins aminosalicylates amylin analogsAnalgesic Combinations Analgesics androgens and anabolic steroidsangiotensin converting enzyme inhibitors angiotensin II inhibitorsanorectal preparations anorexiants antacids anthelminticsanti-angiogenic ophthalmic agents anti-CTLA-4 monoclonal antibodiesanti-infectives antiadrenergic agents, centrally acting antiadrenergicagents, peripherally acting antiandrogens antianginal agentsantiarrhythmic agents antiasthmatic combinationsantibiotics/antineoplastics anticholinergic antiemetics anticholinergicantiparkinson agents anticholinergic bronchodilators anticholinergicchronotropic agents anticholinergics/antispasmodics anticoagulantsanticonvulsants antidepressants antidiabetic agents antidiabeticcombinations antidiarrheals antidiuretic hormones antidotesantiemetic/antivertigo agents antifungals antigonadotropic agentsantigout agents antihistamines antihyperlipidemic agentsantihyperlipidemic combinations antihypertensive combinationsantihyperuricemic agents antimalarial agents antimalarial combinationsantimalarial quinolines antimetabolites antimigraine agentsantineoplastic detoxifying agents antineoplastic interferonsantineoplastic monoclonal antibodies antineoplastics antiparkinsonagents antiplatelet agents antipseudomonal penicillins antipsoriaticsantipsychotics antirheumatics antiseptic and germicides antithyroidagents antitoxins and antivenins antituberculosis agentsantituberculosis combinations antitussives antiviral agents antiviralcombinations antiviral interferons anxiolytics, sedatives, and hypnoticsaromatase inhibitors atypical antipsychotics azole antifungals bacterialvaccines barbiturate anticonvulsants barbiturates BCR-ABL tyrosinekinase inhibitors benzodiazepine anticonvulsants benzodiazepinesbeta-adrenergic blocking agents beta-lactamase inhibitors bile acidsequestrants biologicals bisphosphonates bone resorption inhibitorsbronchodilator combinations bronchodilators calcitonin calcium channelblocking agents carbamate anticonvulsants carbapenems carbonic anhydraseinhibitor anticonvulsants carbonic anhydrase inhibitors cardiacstressing agents cardioselective beta blockers cardiovascular agentscatecholamines CD₂O monoclonal antibodies CD33 monoclonal antibodiesCD52 monoclonal antibodies central nervous system agents cephalosporinscerumenolytics chelating agents chemokine receptor antagonist chloridechannel activators cholesterol absorption inhibitors cholinergicagonists cholinergic muscle stimulants cholinesterase inhibitors CNSstimulants coagulation modifiers colony stimulating factorscontraceptives corticotropin coumarins and indandiones cox-2 inhibitorsdecongestants dermatological agents diagnostic radiopharmaceuticalsdibenzazepine anticonvulsants digestive enzymes dipeptidyl peptidase 4inhibitors diuretics dopaminergic antiparkinsonism agents drugs used inalcohol dependence echinocandins EGFR inhibitors estrogen receptorantagonists estrogens expectorants factor Xa inhibitors fatty acidderivative anticonvulsants fibric acid derivatives first generationcephalosporins fourth generation cephalosporins functional boweldisorder agents gallstone solubilizing agents gamma-aminobutyric acidanalogs gamma-aminobutyric acid reuptake inhibitors gamma-aminobutyricacid transaminase inhibitors gastrointestinal agents general anestheticsgenitourinary tract agents GI stimulants glucocorticoids glucoseelevating agents glycopeptide antibiotics glycoprotein plateletinhibitors glycylcyclines gonadotropin releasing hormonesgonadotropin-releasing hormone antagonists gonadotropins group Iantiarrhythmics group II antiarrhythmics group III antiarrhythmics groupIV antiarrhythmics group V antiarrhythmics growth hormone receptorblockers growth hormones H. pylori eradication agents H2 antagonistshematopoietic stem cell mobilizer heparin antagonists heparins HER2inhibitors herbal products histone deacetylase inhibitors hormonereplacement therapy hormones hormones/antineoplastics hydantoinanticonvulsants illicit (street) drugs immune globulins immunologicagents immunosuppressive agents impotence agents in vivo diagnosticbiologicals incretin mimetics inhaled anti-infectives inhaledcorticosteroids inotropic agents insulin insulin-like growth factorintegrase strand transfer inhibitor interferons intravenous nutritionalproducts iodinated contrast media ionic iodinated contrast media ironproducts ketolides laxatives leprostatics leukotriene modifierslincomycin derivatives lipoglycopeptides local injectable anestheticsloop diuretics lung surfactants lymphatic staining agents lysosomalenzymes macrolide derivatives macrolides magnetic resonance imagingcontrast media mast cell stabilizers medical gas meglitinides metabolicagents methylxanthines mineralocorticoids minerals and electrolytesmiscellaneous agents miscellaneous analgesics miscellaneous antibioticsmiscellaneous anticonvulsants miscellaneous antidepressantsmiscellaneous antidiabetic agents miscellaneous antiemeticsmiscellaneous antifungals miscellaneous antihyperlipidemic agentsmiscellaneous antimalarials miscellaneous antineoplastics miscellaneousantiparkinson agents miscellaneous antipsychotic agents miscellaneousantituberculosis agents miscellaneous antivirals miscellaneousanxiolytics, sedatives and hypnotics miscellaneous biologicalsmiscellaneous bone resorption inhibitors miscellaneous cardiovascularagents miscellaneous central nervous system agents miscellaneouscoagulation modifiers miscellaneous diuretics miscellaneousgenitourinary tract agents miscellaneous GI agents miscellaneoushormones miscellaneous metabolic agents miscellaneous ophthalmic agentsmiscellaneous otic agents miscellaneous respiratory agents miscellaneoussex hormones miscellaneous topical agents miscellaneous uncategorizedagents miscellaneous vaginal agents mitotic inhibitors monoamine oxidaseinhibitors monoclonal antibodies mouth and throat products mTORinhibitors mTOR kinase inhibitors mucolytics multikinase inhibitorsmuscle relaxants mydriatics narcotic analgesic combinations narcoticanalgesics nasal anti-infectives nasal antihistamines and decongestantsnasal lubricants and irrigations nasal preparations nasal steroidsnatural penicillins neuraminidase inhibitors neuromuscular blockingagents next generation cephalosporins nicotinic acid derivativesnitrates NNRTIs non-cardioselective beta blockers non-iodinated contrastmedia non-ionic iodinated contrast media non-sulfonylureas nonsteroidalanti-inflammatory agents norepinephrine reuptake inhibitorsnorepinephrine-dopamine reuptake inhibitors nucleoside reversetranscriptase inhibitors (NRTIs) nutraceutical products nutritionalproducts ophthalmic anesthetics ophthalmic anti-infectives ophthalmicanti-inflammatory agents ophthalmic antihistamines and decongestantsophthalmic diagnostic agents ophthalmic glaucoma agents ophthalmiclubricants and irrigations ophthalmic preparations ophthalmic steroidsophthalmic steroids with anti-infectives ophthalmic surgical agents oralnutritional supplements otic anesthetics otic anti-infectives oticpreparations otic steroids otic steroids with anti-infectivesoxazolidinedione anticonvulsants parathyroid hormone and analogspenicillinase resistant penicillins penicillins peripheral opioidreceptor antagonists peripheral vasodilators peripherally actingantiobesity agents phenothiazine antiemetics phenothiazineantipsychotics phenylpiperazine antidepressants plasma expandersplatelet aggregation inhibitors platelet-stimulating agents polyenespotassium-sparing diuretics probiotics progesterone receptor modulatorsprogestins prolactin inhibitors prostaglandin D2 antagonists proteaseinhibitors proton pump inhibitors psoralens psychotherapeutic agentspsychotherapeutic combinations purine nucleosides pyrrolidineanticonvulsants quinolones radiocontrast agents radiologic adjunctsradiologic agents radiologic conjugating agents radiopharmaceuticalsRANK ligand inhibitors recombinant human erythropoietins renininhibitors respiratory agents respiratory inhalant products rifamycinderivatives salicylates sclerosing agents second generationcephalosporins selective estrogen receptor modulators selectiveserotonin reuptake inhibitors serotonin-norepinephrine reuptakeinhibitors serotoninergic neuroenteric modulators sex hormonecombinations sex hormones skeletal muscle relaxant combinations skeletalmuscle relaxants smoking cessation agents somatostatin and somatostatinanalogs spermicides statins sterile irrigating solutions streptomycesderivatives succinimide anticonvulsants sulfonamides sulfonylureassynthetic ovulation stimulants tetracyclic antidepressants tetracyclinestherapeutic radiopharmaceuticals thiazide diuretics thiazolidinedionesthioxanthenes third generation cephalosporins thrombin inhibitorsthrombolytics thyroid drugs tocolytic agents topical acne agents topicalagents topical anesthetics topical anti-infectives topical antibioticstopical antifungals topical antihistamines topical antipsoriaticstopical antivirals topical astringents topical debriding agents topicaldepigmenting agents topical emollients topical keratolytics topicalsteroids topical steroids with anti-infectives toxoids triazineanticonvulsants tricyclic antidepressants trifunctional monoclonalantibodies tumor necrosis factor (TNF) inhibitors tyrosine kinaseinhibitors ultrasound contrast media upper respiratory combinations ureaanticonvulsants urinary anti-infectives urinary antispasmodics urinarypH modifiers uterotonic agents vaccine vaccine combinations vaginalanti-infectives vaginal preparations vasodilators vasopressinantagonists vasopressors VEGFNEGFR inhibitors viral vaccinesviscosupplementation agents vitamin and mineral combinations vitaminsDiagnostic Tests 17-Hydroxyprogesterone ACE (Angiotensin I convertingenzyme) Acetaminophen Acid phosphatase ACTH Activated clotting timeActivated protein C resistance Adrenocorticotropic hormone (ACTH)Alanine aminotransferase (ALT) Albumin Aldolase Aldosterone Alkalinephosphatase Alkaline phosphatase (ALP) Alpha1-antitrypsinAlpha-fetoprotein Alpha-fetoprotien Ammonia levels Amylase ANA(antinuclear antbodies) ANA (antinuclear antibodies)Angiotensin-converting enzyme (ACE) Anion gap Anticardiolipin antibodyAnticardiolipin antivbodies (ACA) Anti-centromere antibody Antidiuretichormone Anti-DNA Anti-Dnase-B Anti-Gliadin antibody Anti-glomerularbasement membrane antibody Anti-HBc (Hepatitis B core antibodiesAnti-HBs (Hepatitis B surface antibody Antiphospholipid antibodyAnti-RNA polymerase Anti-Smith (Sm) antibodies Anti-Smooth Muscleantibody Antistreptolysin O (ASO) Antithrombin III Anti-Xa activityAnti-Xa assay Apolipoproteins Arsenic Aspartate aminotransferase (AST)B12 Basophil Beta-2-Microglobulin Beta-hydroxybutyrate B-HCG BilirubinBilirubin, direct Bilirubin, indirect Bilirubin, total Bleeding timeBlood gases (arterial) Blood urea nitrogen (BUN) BUN BUN (blood ureanitrogen) CA 125 CA 15-3 CA 19-9 Calcitonin Calcium Calcium (ionized)Carbon monoxide (CO) Carcinoembryonic antigen (CEA) CBC CEA CEA(carcinoembryonic antigen) Ceruloplasmin CHSOChloride CholesterolCholesterol, HDL Clot lysis time Clot retraction time CMP CO₂ Coldagglutinins Complement C3 Copper Corticotrophin releasing hormone (CRH)stimulation test Cortisol Cortrosyn stimulation test C-peptide CPK(Total) CPK-MB C-reactive protein Creatinine Creatinine kinase (CK)Cryoglobulins DAT (Direct antiglobulin test) D-Dimer Dexamethasonesuppression test DHEA-S Dilute Russell viper venom Elliptocytes.Eosinophil Erythrocyte sedimentation rate (ESR) Estradiol EstriolEthanol Ethylene glycol Euglobulin lysis Factor V Leiden Factor VIIIinhibitor Factor VIII level Ferritin Fibrin split products FibrinogenFolate Folate (serum Fractional excretion of sodium (FENA) FSH (folliclestimulating factor) FTA-ABS Gamma glutamyl transferase (GGT) GastrinGGTP (Gamma glutamyl transferase) Glucose Growth hormone HaptoglobinHBeAg (Hepatitis Be antigen) HBs-Ag (Hepatitis B surface antigen)Helicobacter pylori Hematocrit Hematocrit (HCT) Hemoglobin HemoglobinA1C Hemoglobin electrophoresis Hepatitis A antibodies Hepatitis Cantibodies IAT (Indirect antiglobulin test) Immunofixation (IFE) IronLactate dehydrogenase (LDH) Lactic acid (lactate) LDH LH (Leutinizinghormone Lipase Lupus anticoagulant Lymphocyte Magnesium MCH (meancorpuscular hemoglobin MCHC (mean corpuscular hemoglobin concentration)MCV (mean corpuscular volume) Methylmalonate Monocyte MPV (mean plateletvolume) Myoglobin Neutrophil Parathyroid hormone (PTH) PhosphorusPlatelets (pit) Potassium Prealbumin Prolactin Prostate specific antigen(PSA) Protein C Protein S PSA (prostate specific antigen) PT(Prothrombin time) PTT (Partial thromboplastin time) RDW (red celldistribution width) Renin Rennin Reticulocyte count reticulocytesRheumatoid factor (RF) Sed Rate Serum glutamic-pyruvic transaminase(SGPT Serum protein electrophoresis (SPEP) Sodium T3-resin uptake (T3RU)T4, Free Thrombin time Thyroid stimulating hormone (TSH) Thyroxine (T4Total iron binding capacity (TIBC) Total protein Transferrin Transferrinsaturation Triglyceride (TG) Troponin Uric acid Vitamin B12 White bloodcells (WBC) Widal test Inhalation Anesthetics Aliflurane ChloroformCyclopropane Desflurane (Suprane) Diethyl Ether Enflurane (Ethrane)Ethyl Chloride Ethylene Halothane (Fluothane) Isoflurane (Forane,Isoflo) Isopropenyl vinyl ether Methoxyflurane methoxyflurane,Methoxypropane Nitrous Oxide Roflurane Sevoflurane (Sevorane, Ultane,Sevoflo) Teflurane Trichloroethylene Vinyl Ether Xenon